81,076 results on '"Epigenesis, Genetic"'
Search Results
2. Targeting NPM1 Epigenetically Promotes Postinfarction Cardiac Repair by Reprogramming Reparative Macrophage Metabolism.
- Author
-
Zhang, Sheng, Zhang, Yunkai, Duan, Xuewen, Wang, Bo, and Zhan, Zhenzhen
- Subjects
- *
OLIGONUCLEOTIDES , *MONONUCLEAR leukocytes , *METABOLIC reprogramming , *PHENOTYPIC plasticity , *MYOCARDIAL infarction , *MACROPHAGES - Abstract
BACKGROUND: Reparative macrophages play a crucial role in limiting excessive fibrosis and promoting cardiac repair after myocardial infarction (MI), highlighting the significance of enhancing their reparative phenotype for wound healing. Metabolic adaptation orchestrates the phenotypic transition of macrophages; however, the precise mechanisms governing metabolic reprogramming of cardiac reparative macrophages remain poorly understood. In this study, we investigated the role of NPM1 (nucleophosmin 1) in the metabolic and phenotypic shift of cardiac macrophages in the context of MI and explored the therapeutic effect of targeting NPM1 for ischemic tissue repair. METHODS: Peripheral blood mononuclear cells were obtained from healthy individuals and patients with MI to explore NPM1 expression and its correlation with prognostic indicators. Through RNA sequencing, metabolite profiling, histology, and phenotype analyses, we investigated the role of NPM1 in postinfarct cardiac repair using macrophage-specific NPM1 knockout mice. Epigenetic experiments were conducted to study the mechanisms underlying metabolic reprogramming and phenotype transition of NPM1-deficient cardiac macrophages. The therapeutic efficacy of antisense oligonucleotide and inhibitor targeting NPM1 was then assessed in wild-type mice with MI. RESULTS: NPM1 expression was upregulated in the peripheral blood mononuclear cells from patients with MI that closely correlated with adverse prognostic indicators of MI. Macrophage-specific NPM1 deletion reduced infarct size, promoted angiogenesis, and suppressed tissue fibrosis, in turn improving cardiac function and protecting against adverse cardiac remodeling after MI. Furthermore, NPM1 deficiency boosted the reparative function of cardiac macrophages by shifting macrophage metabolism from the inflammatory glycolytic system to oxygen-driven mitochondrial energy production. The oligomeric NPM1 recruited histone demethylase KDM5b to the promoter of Tsc1 (TSC complex subunit 1), the mTOR (mechanistic target of rapamycin kinase) complex inhibitor, reduced histone H3K4me3 modification, and inhibited TSC1 expression, which then facilitated mTOR-related inflammatory glycolysis and antagonized the reparative function of cardiac macrophages. The in vivo administration of antisense oligonucleotide targeting NPM1 or oligomerization inhibitor NSC348884 substantially ameliorated tissue injury and enhanced cardiac recovery in mice after MI. CONCLUSIONS: Our findings uncover the key role of epigenetic factor NPM1 in impeding postinfarction cardiac repair by remodeling metabolism pattern and impairing the reparative function of cardiac macrophages. NPM1 may serve as a promising prognostic biomarker and a valuable therapeutic target for heart failure after MI. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
3. Adverse Childhood Experiences, Adaptation and Breast Cancer (CAPONE)
- Author
-
Ligue contre le cancer, France and Christine Rotonda, Director of the research pole in Pierre Janet Center
- Published
- 2023
4. Effects of valproic acid on wound healing of the abdominal wall musculoaponeurotic layer: an experimental study in rats
- Author
-
RACHEL BIONDO SIMÕES, MARIA DE LOURDES PESSOLE BIONDO SIMÕES, SÉRGIO OSSAMU IOSHII, ROGÉRIO RIBEIRO ROBES, MOACIR OLIVEIRA DALL’ANTONIA, MATHEUS PRINCE GOEHR, and PEDRO JUAN FURTADO NEVES
- Subjects
Valproic Acid ,Epigenesis, Genetic ,Wound healing ,Abdominal Wall ,Surgery ,RD1-811 - Abstract
ABSTRACT Introduction: valproic acid (VPA), an epigenetic drug, has potential for the treatment of neoplasms. Its effects on the healing of the peritoneal-musculo-aponeurotic plane (PMA) of the abdominal wall are studied. Method: sixty Wistar rats were allocated into two groups: experimental (VPA) and control (0.9% sodium chloride), treated daily, starting three days before the intervention and until euthanasia. Under anesthesia, a median laparotomy was performed and repaired with two synthetic layers. Assessments took place 3, 7 and 14 days after surgery. The integrity of the wounds, the quality of the inflammatory reaction, the intensity of the leukocyte infiltrate, collagen synthesis, the intensity of angiogenesis and the presence of myofibroblasts were studied. Results: there was dehiscence of the PMA plane in 11 of the 30 animals (p=0.001) in the experimental group. There was no difference in the quality and intensity of the inflammatory reaction. Immunohistochemistry revealed, in the experimental group, less collagen I (p3=0.003, p7=0.013 and p14=0.001) and more collagen III (p3=0.003, p7=0.013 and p14= 0.001). Collagen evaluated by Sirus Supra Red F3BA showed, in the experimental group, less collagen at all three times (p
- Published
- 2024
- Full Text
- View/download PDF
5. Zebrafish Fin: Complex Molecular Interactions and Cellular Mechanisms Guiding Regeneration
- Author
-
Ivonne Sehring and Gilbert Weidinger
- Subjects
Cell type ,Epidermis (botany) ,Regeneration (biology) ,Cell Differentiation ,Biology ,Zebrafish Proteins ,biology.organism_classification ,General Biochemistry, Genetics and Molecular Biology ,Cell biology ,Epigenesis, Genetic ,Animals ,Epigenetics ,Signal transduction ,Progenitor cell ,Blastema ,Zebrafish ,Signal Transduction - Abstract
The zebrafish caudal fin has become a popular model to study cellular and molecular mechanisms of regeneration due to its high regenerative capacity, accessibility for experimental manipulations, and relatively simple anatomy. The formation of a regenerative epidermis and blastema are crucial initial events and tightly regulated. Both the regenerative epidermis and the blastema are highly organized structures containing distinct domains, and several signaling pathways regulate the formation and interaction of these domains. Bone is the major tissue regenerated from the progenitor cells of the blastema. Several cellular mechanisms can provide source cells for blastemal (pre-)osteoblasts, including dedifferentiation of differentiated osteoblasts and de novo formation from other cell types, providing intriguing examples of cellular plasticity. In recent years, omics analyses and single-cell approaches have elucidated genetic and epigenetic regulation, increasing our knowledge of the surprisingly complex coordination of various mechanisms to achieve successful restoration of a seemingly simple structure.
- Published
- 2024
6. Epigenetic Mechanisms of Brain Sexual Differentiation
- Author
-
Bruno Gegenhuber and Jessica Tollkuhn
- Subjects
Male ,Sex Characteristics ,Sex Differentiation ,Estrogen Receptor alpha ,Animals ,Brain ,Female ,General Biochemistry, Genetics and Molecular Biology ,Hormones ,Epigenesis, Genetic - Abstract
Across vertebrate species, gonadal hormones coordinate physiology with behavior to facilitate social interactions essential for reproduction and survival. In adulthood, these hormones activate neural circuits that regulate behaviors presenting differently in females and males, such as parenting and territorial aggression. Yet long before sex-typical behaviors emerge at puberty, transient hormone production during sensitive periods of neurodevelopment establish the circuits upon which adult hormones act. How transitory waves of early-life hormone signaling exert lasting effects on the brain remains a central question. Here we discuss how perinatal estradiol signaling organizes cellular and molecular sex differences in the rodent brain. We review classic anatomic studies revealing sex differences in cell number, volume, and neuronal projections, and consider how single-cell sequencing methods enable distinction between sex-biased cell-type abundance and gene expression. Finally, we highlight the recent discovery of a gene regulatory program activated by estrogen receptor α (ERα) following the perinatal hormone surge. A subset of this program displays sustained sex-biased gene expression and chromatin accessibility throughout the postnatal sensitive period, demonstrating a bona fide epigenetic mechanism. We propose that ERα-expressing neurons throughout the social behavior network use similar gene regulatory programs to coordinate brain sexual differentiation.
- Published
- 2024
7. Valproic acid and bladder healing: an experimental study in rats
- Author
-
MARIA DE LOURDES PESSOLE BIONDO-SIMÕES, MOACIR OLIVEIRA DALL’ANTONIA, MATHEUS PRINCE GOEHR, RACHEL BIONDO-SIMÕES, SÉRGIO OSSAMU IOSHII, and ROGÉRIO RIBEIRO ROBES
- Subjects
Valproic Acid ,Wound Healing ,Epigenesis, Genetic ,Cell Proliferation ,Urinary Bladder ,Surgery ,RD1-811 - Abstract
ABSTRACT Purpose: to recognize the effects of valproic acid (VPA), an epigenetic drug, on the bladder healing process, in rats. Method: twenty male Wistar rats were divided in two groups: experimental (A), treated with VPA (150mg/Kg/day), and control (B) with 0.9% sodium chloridrate. Healing was analyzed on the third and seventh days, evaluating the inflammatory reaction, collagen synthesis and angiogenesis. Results: inflammatory reaction on the third day was minimal and acute in both groups. On the seventh day, it was subacute in both groups, moderate intensity in group A and minimal in group B (p=0.0476). Collagen III intensity, marked by immunohistochemistry, was similar in both groups. Collagen I intensity on the third day was similar in both groups, but on the seventh day it was higher in experimental than control (p=0.0476). Collagen evaluation by picrosiriusred allowed to verify that the presence of collagen III was similar in both groups (p=0.3312) on the third day, and it was higher in control on the seventh day (p=0.0015). Collagen I showed similarity on the third day (p=0.3100), and it was higher in control on the seventh day (p=0.0015). Vessel marked with anti-SMA counting showed fewer vessels on the third (p=0.0034) and seventh day (p=0.0087) in experimental group. The lower intensity of angiogenesis was confirmed with anti-CD34, on the third day (p=0,0006) and on the seventh day (p=0,0072). Conclusion: VPA determined alterations in the bladder healing process, in rats, with lower collagen density and less angiogenic activity, but without compromising the integrity of the organ.
- Published
- 2022
- Full Text
- View/download PDF
8. Epigenetic Reprogramming in Early Animal Development
- Author
-
Zhenhai Du, Wei Xie, and Ke Zhang
- Subjects
Epigenomics ,Zygote ,Totipotent ,Embryonic Development ,Gene Expression Regulation, Developmental ,Embryo ,Epigenome ,Biology ,Cellular Reprogramming ,General Biochemistry, Genetics and Molecular Biology ,Chromatin ,Cell biology ,Epigenesis, Genetic ,medicine.anatomical_structure ,medicine ,Gamete ,Animals ,Reprogramming ,Gametogenesis - Abstract
Dramatic nuclear reorganization occurs during early development to convert terminally differentiated gametes to a totipotent zygote, which then gives rise to an embryo. Aberrant epigenome resetting severely impairs embryo development and even leads to lethality. How the epigenomes are inherited, reprogrammed, and reestablished in this critical developmental period has gradually been unveiled through the rapid development of technologies including ultrasensitive chromatin analysis methods. In this review, we summarize the latest findings on epigenetic reprogramming in gametogenesis and embryogenesis, and how it contributes to gamete maturation and parental-to-zygotic transition. Finally, we highlight the key questions that remain to be answered to fully understand chromatin regulation and nuclear reprogramming in early development.
- Published
- 2024
9. Comparative DNA methylation reveals epigenetic adaptation to high altitude in snub-nosed monkeys.
- Author
-
Wang L, Liu WQ, Du J, Li M, Wu RF, and Li M
- Subjects
- Animals, Adaptation, Physiological genetics, Colobinae genetics, Colobinae physiology, DNA Methylation, Altitude, Epigenesis, Genetic
- Abstract
DNA methylation plays a crucial role in environmental adaptations. Here, using whole-genome bisulfite sequencing, we generated comprehensive genome-wide DNA methylation profiles for the high-altitude Yunnan snub-nosed monkey ( Rhinopithecus bieti ) and the closely related golden snub-nosed monkey ( R. roxellana ). Our findings indicated a slight increase in overall DNA methylation levels in golden snub-nosed monkeys compared to Yunnan snub-nosed monkeys, suggesting a higher prevalence of hypermethylated genomic regions in the former. Comparative genomic methylation analysis demonstrated that genes associated with differentially methylated regions were involved in membrane fusion, vesicular formation and trafficking, hemoglobin function, cell cycle regulation, and neuronal differentiation. These results suggest that the high-altitude-related epigenetic modifications are extensive, involving a complete adaptation process from the inhibition of single Ca
2+ channel proteins to multiple proteins collaboratively enhancing vesicular function or inhibiting cell differentiation and proliferation. Functional assays demonstrated that overexpression or down-regulation of candidate genes, such as SNX10 , TIMELESS , and CACYBP , influenced cell viability under stress conditions. Overall, this research suggests that comparing DNA methylation across closely related species can identify novel candidate genomic regions and genes associated with local adaptations, thereby deepening our understanding of the mechanisms underlying environmental adaptations.- Published
- 2024
- Full Text
- View/download PDF
10. Epigenetic Regulation of Neural Activity in the Depressed Brain: The Two Faces of the Histone Deacetylase SIRT1.
- Author
-
Torres-Berrío A
- Subjects
- Humans, Animals, Sirtuin 1 genetics, Sirtuin 1 metabolism, Epigenesis, Genetic, Brain
- Published
- 2024
- Full Text
- View/download PDF
11. Epigenetic regulation in liver regeneration.
- Author
-
Li Z and Sun X
- Subjects
- Humans, Animals, Liver metabolism, Liver physiology, Hepatocytes metabolism, Hepatocytes physiology, Cell Proliferation genetics, Liver Regeneration genetics, Liver Regeneration physiology, Epigenesis, Genetic
- Abstract
The liver is considered unique in its enormous capacity for regeneration and self-repair. In contrast to other regenerative organs (i.e., skin, skeletal muscle, and intestine), whether the adult liver contains a defined department of stem cells is still controversial. In order to compensate for the massive loss of hepatocytes following liver injury, the liver processes a precisely controlled transcriptional reprogram that can trigger cell proliferation and cell-fate switch. Epigenetic events are thought to regulate the organization of chromatin architecture and gene transcription during the liver regenerative process. In this review, we will summarize how changes to the chromatin by epigenetic modifiers are translated into cell fate transitions to restore liver homeostasis during liver regeneration., Competing Interests: Declaration of competing interest All authors disclosed no financial relationships relevant to this publication., (Copyright © 2024. Published by Elsevier Inc.)
- Published
- 2024
- Full Text
- View/download PDF
12. Epigenetic regulation of cGAS and STING expression in cancer.
- Author
-
Zhao C, Guo S, and Ge S
- Subjects
- Humans, Animals, Signal Transduction, Gene Expression Regulation, Neoplastic, Immunity, Innate genetics, Nucleotidyltransferases genetics, Nucleotidyltransferases metabolism, Neoplasms genetics, Neoplasms immunology, Neoplasms therapy, Neoplasms metabolism, Epigenesis, Genetic, Membrane Proteins genetics, Membrane Proteins metabolism, Immunotherapy methods
- Abstract
Although cancer immunotherapy has become a successful therapeutic strategy in a certain range of solid cancer and hematological malignancies, this efficacy of immunotherapy is impeded by limited success rates due to an immunologically "cold" state. The cGAS-STING signaling pathway is an evolutionarily conserved system which can find cytoplasmic DNA to regulate the innate immune and adaptive immune response. Beyond the host defense and autoimmune disorders, recent advances have now expanded the roles of cGAS-STING that is precise activated and tight regulated to improve anticancer immunity. Mounting evidence now has shown the crucial role of epigenetic regulation in mediating the expression of key genes associated with the cGAS-STING signaling pathway. In this review, we highlight the structure and cellular localization of cGAS and STING as well as intracellular cascade reaction of cGAS-STING signal transduction. We further summarize recent findings of epigenetic regulatory mechanisms that control the expression of cGAS and STING in cancer. The review aims to offer theoretical basis and reference for targeting the epigenetic mechanisms that control cGAS and STING gene expression to promote the development of more effective combination therapeutic regimens to enhance the efficacy of cancer immunotherapy in clinical practice and cancer clinical and cancer research workers., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)
- Published
- 2024
- Full Text
- View/download PDF
13. The DNA methylation landscape across the TCR loci in patients with acute myeloid leukemia.
- Author
-
Pospiech M, Beckford J, Kumar AMS, Tamizharasan M, Brito J, Liang G, Mangul S, and Alachkar H
- Subjects
- Humans, Decitabine pharmacology, Decitabine therapeutic use, Receptors, Antigen, T-Cell genetics, T-Lymphocytes immunology, Epigenesis, Genetic, Antimetabolites, Antineoplastic therapeutic use, Antimetabolites, Antineoplastic pharmacology, DNA Methylation, Leukemia, Myeloid, Acute genetics, Leukemia, Myeloid, Acute drug therapy, Leukemia, Myeloid, Acute immunology
- Abstract
The capacity of T cells to initiate anti-leukemia immune responses is determined by the ability of their receptors (TCRs) to recognize leukemia neoantigens. Epigenetic mechanisms including DNA methylation contribute to shaping the TCR repertoire composition and diversity. The DNA hypomethylating agents (HMAs) have been widely used in the treatment of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Whether DNA HMAs directly influence TCR gene loci methylation patterns remains unknown. By analyzing public datasets, we compared methylation patterns across TCR loci in AML patients and healthy controls. We also explored how HMAs influence TCR loci DNA methylation in patients with AML. While methylation patterns are largely conserved across the TCR loci, certain V genes exhibit high interindividual variability. Although overall methylation levels within the TCR loci did not show significant differences, specific sites, including 32 TRAV and 12 TRBV sites exhibited distinct methylation patterns when comparing T cells from healthy donors to those from patients with AML. In leukemic cells, decitabine treatment demethylates sites across the TRAV and TRBV genes. While not as significant, a similar pattern of demethylation is observed in T cells. Pretreatment AML samples exhibit higher methylation beta values in differentially methylated positions (DMPs) compared with non-DMPs. Methylation levels of certain TRAV and TRBV genes in leukemic cells are associated with patients' risk status. The presence of disease specific TCR loci methylated signatures that are associated with clinical outcome presents an opportunity for therapeutic intervention. HMAs can modulate the TCR loci methylation patterns, yet whether they could reprogram the TCR repertoire composition remains to be explored., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)
- Published
- 2024
- Full Text
- View/download PDF
14. Epigenetic aging in major depressive disorder: Clocks, mechanisms and therapeutic perspectives.
- Author
-
Shaikh M and Doshi G
- Subjects
- Humans, Animals, Antidepressive Agents therapeutic use, Antidepressive Agents pharmacology, Depressive Disorder, Major drug therapy, Depressive Disorder, Major genetics, Epigenesis, Genetic, Aging genetics
- Abstract
Depression, a chronic mental disorder characterized by persistent sadness, loss of interest, and difficulty in daily tasks, impacts millions globally with varying treatment options. Antidepressants, despite their long half-life and minimal effectiveness, leave half of patients undertreated, highlighting the need for new therapies to enhance well-being. Epigenetics, which studies genetic changes in gene expression or cellular phenotype without altering the underlying Deoxyribonucleic Acid (DNA) sequence, is explored in this article. This article delves into the intricate relationship between epigenetic mechanisms and depression, shedding light on how environmental stressors, early-life adversity, and genetic predispositions shape gene expression patterns associated with depression. We have also discussed Histone Deacetylase (HDAC) inhibitors, which enhance cognitive function and mood regulation in depression. Non-coding RNAs, (ncRNAs) such as Long Non-Coding RNAs (lncRNAs) and micro RNA (miRNAs), are highlighted as potential biomarkers for detecting and monitoring major depressive disorder (MDD). This article also emphasizes the reversible nature of epigenetic modifications and their influence on neuronal growth processes, underscoring the dynamic interplay between genetics, environment, and epigenetics in depression development. It explores the therapeutic potential of targeting epigenetic pathways in treating clinical depression. Additionally, it examines clinical findings related to epigenetic clocks and their role in studying depression and biological aging., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)
- Published
- 2024
- Full Text
- View/download PDF
15. Immunological hide-and-seek: epigenetically reprogrammed cancer cells and the dynamics of CD8 + T cells.
- Author
-
Low JT, Chan MWY, Shen CH, and Wei KL
- Subjects
- Humans, Immunotherapy methods, Tumor Escape genetics, Animals, Epigenesis, Genetic, Tumor Microenvironment immunology, Tumor Microenvironment genetics, Neoplasms immunology, Neoplasms genetics, CD8-Positive T-Lymphocytes immunology
- Abstract
Cancer remains a global health burden, shaped by both genetic mutations and epigenetic dysregulation. Epigenetic alteration plays a pivotal role in tumorigenesis, immune response modulation, and the emergence of treatment resistance. This review emphasizes the intricate interplay between epigenetically reprogrammed cancer cells and the tumor microenvironment (TME), a relationship central to the immunoediting concept, which encompasses elimination, equilibrium, and escape phases. This review highlights the significance of CD8
+ T cells as potent anticancer agents and discusses the mechanisms by which tumor cells evade immune surveillance and evolve resistance to immunotherapy. Such evasion entails the regulation of inhibitory molecules, antigen presentation machinery, and cytokine milieu. Furthermore, this review explores the complex dynamics culminating in CD8+ T cell dysfunction within the TME. In summary, this work offers insights into the indispensable role of epigenetic mechanisms in bolstering cancer cell survival amidst immunological challenges within the TME., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)- Published
- 2024
- Full Text
- View/download PDF
16. Intrinsic Epigenetic State of Primary Osteosarcoma Drives Metastasis.
- Author
-
Singh I, Rainusso N, Kurenbekova L, Nirala BK, Dou J, Muruganandham A, and Yustein JT
- Subjects
- Humans, Cell Line, Tumor, Gene Expression Regulation, Neoplastic, Mice, Chromatin genetics, Chromatin metabolism, Cell Proliferation genetics, Osteosarcoma genetics, Osteosarcoma pathology, Epigenesis, Genetic, Bone Neoplasms genetics, Bone Neoplasms pathology, Neoplasm Metastasis
- Abstract
Osteosarcoma is the most common primary malignant bone tumor affecting the pediatric population with a high potential to metastasize. However, insights into the molecular features enabling its metastatic potential are limited. We mapped the active chromatin landscapes of osteosarcoma tumors by integrating histone H3 lysine-acetylated chromatin state (n = 13), chromatin accessibility profiles (n = 11), and gene expression (n = 13) to understand the differences in their active chromatin profiles and their impact on molecular mechanisms driving the malignant phenotypes. Primary osteosarcoma tumors from patients with metastasis (primary met) have a distinct active chromatin landscape compared with those without metastasis (localized). This difference shapes the transcriptional profile of osteosarcoma. We identified novel candidate genes, including PPP1R1B, PREX1, and IGF2BP1, that exhibit increased chromatin activity in primary met. Loss of PREX1 in primary met osteosarcoma cells significantly diminishes osteosarcoma proliferation, invasion, migration, and colony formation capacity. Differential chromatin activity in primary met is associated with genes regulating cytoskeleton organization, cellular adhesion, and extracellular matrix, suggesting their role in facilitating osteosarcoma metastasis. Chromatin profiling of tumors from metastatic lung lesions shows increased chromatin activity in genes involved in cell migration and Wnt pathway. These data demonstrate that metastatic potential is intrinsically present in primary met tumors, with cellular chromatin profiles further adapting for successful dissemination, migration, and colonization at the distal site. Implications: Our study demonstrates that metastatic potential is intrinsic to primary metastatic osteosarcoma tumors, with chromatin profiles further adapting for successful dissemination, migration, and colonization at the distal metastatic site., (©2024 American Association for Cancer Research.)
- Published
- 2024
- Full Text
- View/download PDF
17. USP44 Overexpression Drives a MYC-Like Gene Expression Program in Neuroblastoma through Epigenetic Reprogramming.
- Author
-
Ekstrom TL, Hussain S, Bedekovics T, Ali A, Paolini L, Mahmood H, Rosok RM, Koster J, Johnsen SA, and Galardy PJ
- Subjects
- Humans, Cell Line, Tumor, Mice, Animals, Proto-Oncogene Proteins c-myc metabolism, Proto-Oncogene Proteins c-myc genetics, Cell Proliferation genetics, Neuroblastoma genetics, Neuroblastoma pathology, Neuroblastoma metabolism, Ubiquitin Thiolesterase genetics, Ubiquitin Thiolesterase metabolism, Epigenesis, Genetic, Gene Expression Regulation, Neoplastic
- Abstract
Neuroblastoma is an embryonic cancer that contributes disproportionately to death in young children. Sequencing data have uncovered few recurrently mutated genes in this cancer, although epigenetic pathways have been implicated in disease pathogenesis. We used an expression-based computational screen that examined the impact of deubiquitinating enzymes on patient survival to identify potential new targets. We identified the histone H2B deubiquitinating enzyme USP44 as the enzyme with the greatest impact on survival in patients with neuroblastoma. High levels of USP44 significantly correlate with metastatic disease, unfavorable histology, advanced patient age, and MYCN amplification. The subset of patients with tumors expressing high levels of USP44 had significantly worse survival, including those with tumors lacking MYCN amplification. We showed experimentally that USP44 regulates neuroblastoma cell proliferation, migration, invasion, and neuronal development. Depletion of the histone H2B ubiquitin ligase subunit RNF20 resulted in similar findings, strongly implicating this histone mark as the target of USP44 activity in this disease. Integration of transcriptome and epigenome in analyses demonstrates a distinct set of genes that are regulated by USP44, including those in Hallmark MYC target genes in both murine embryonic fibroblasts and the SH-SY5Y neuroblastoma cell line. We conclude that USP44 is a novel epigenetic regulator that promotes aggressive features and may be a novel target in neuroblastoma. Implications: This study identifies a new genetic marker of aggressive neuroblastoma and identifies the mechanisms by which its overactivity contributes to the pathophysiology of this disease., (©2024 The Authors; Published by the American Association for Cancer Research.)
- Published
- 2024
- Full Text
- View/download PDF
18. Improved simultaneous mapping of epigenetic features and 3D chromatin structure via ViCAR.
- Author
-
Flynn SM, Dhir S, Herka K, Doyle C, Melidis L, Simeone A, Hui WWI, Araujo Tavares RC, Schoenfelder S, Tannahill D, and Balasubramanian S
- Subjects
- Humans, Epigenomics methods, Histone Code, Histones metabolism, Chromatin metabolism, Epigenesis, Genetic, G-Quadruplexes
- Abstract
Methods to measure chromatin contacts at genomic regions bound by histone modifications or proteins are important tools to investigate chromatin organization. However, such methods do not capture the possible involvement of other epigenomic features such as G-quadruplex DNA secondary structures (G4s). To bridge this gap, we introduce ViCAR (viewpoint HiCAR), for the direct antibody-based capture of chromatin interactions at folded G4s. Through ViCAR, we showcase the first G4-3D interaction landscape. Using histone marks, we also demonstrate how ViCAR improves on earlier approaches yielding increased signal-to-noise. ViCAR is a practical and powerful tool to explore epigenetic marks and 3D genome interactomes., (© 2024. The Author(s).)
- Published
- 2024
- Full Text
- View/download PDF
19. Imprinted X chromosome inactivation in marsupials: The paternal X arrives at the egg with a silent DNA methylation profile.
- Author
-
Milton AM, Marín-Gual L, Lister NC, McIntyre KL, Grady PGS, Laird MK, Bond DM, Hore TA, O'Neill RJ, Pask AJ, Renfree MB, Ruiz-Herrera A, and Waters PD
- Subjects
- Animals, Male, Female, Genomic Imprinting, Spermatogenesis genetics, Macropodidae genetics, Ovum metabolism, Marsupialia genetics, Spermatozoa metabolism, Epigenesis, Genetic, DNA Methylation, X Chromosome Inactivation genetics, X Chromosome genetics
- Abstract
X chromosome inactivation (XCI) is an epigenetic process that results in the transcriptional silencing of one X chromosome in the somatic cells of females. This phenomenon is common to both eutherian and marsupial mammals, but there are fundamental differences. In eutherians, the X chosen for silencing is random. DNA methylation on the eutherian inactive X is high at transcription start sites (TSSs) and their flanking regions, resulting in universally high DNA methylation. This contrasts XCI in marsupials where the paternally derived X is always silenced, and in which DNA methylation is low at TSSs and flanking regions. Here, we examined the DNA methylation status of the tammar wallaby X chromosome during spermatogenesis to determine the DNA methylation profile of the paternal X prior to and at fertilization. Whole genome enzymatic methylation sequencing was carried out on enriched flow-sorted populations of premeiotic, meiotic, and postmeiotic cells. We observed that the X displayed a pattern of DNA methylation from spermatogonia to mature sperm that reflected the inactive X in female somatic tissue. Therefore, the paternal X chromosome arrives at the egg with a DNA methylation profile that reflects the transcriptionally silent X in adult female somatic tissue. We present this epigenetic signature as a candidate for the long sought-after imprint for paternal XCI in marsupials., Competing Interests: Competing interests statement:The authors declare no competing interest.
- Published
- 2024
- Full Text
- View/download PDF
20. Unravelling DNA methylation dynamics during developmental stages in Quercus ilex subsp. ballota [Desf.] Samp.
- Author
-
Labella-Ortega M, Martín C, Valledor L, Castiglione S, Castillejo MÁ, Jorrín-Novo JV, and Rey MD
- Subjects
- Gene Expression Regulation, Plant, Plant Leaves genetics, Plant Leaves growth & development, Plant Leaves metabolism, Epigenesis, Genetic, Seedlings genetics, Seedlings growth & development, Genome, Plant, DNA Methylation, Quercus genetics, Quercus growth & development
- Abstract
Background: DNA methylation is a critical factor influencing plant growth, adaptability, and phenotypic plasticity. While extensively studied in model and crop species, it remains relatively unexplored in holm oak and other non-domesticated forest trees. This study conducts a comprehensive in-silico mining of DNA methyltransferase and demethylase genes within the holm oak genome to enhance our understanding of this essential process in these understudied species. The expression levels of these genes in adult and seedling leaves, as well as embryos, were analysed using quantitative real-time PCR (qRT-PCR). Global DNA methylation patterns were assessed through methylation-sensitive amplified polymorphism (MSAP) techniques. Furthermore, specific methylated genomic sequences were identified via MSAP sequencing (MSAP-Seq)., Result: A total of 13 DNA methyltransferase and three demethylase genes were revealed in the holm oak genome. Expression levels of these genes varied significantly between organs and developmental stages. MSAP analyses revealed a predominance of epigenetic over genetic variation among organs and developmental stages, with significantly higher global DNA methylation levels observed in adult leaves. Embryos exhibited frequent demethylation events, while de novo methylation was prevalent in seedling leaves. Approximately 35% of the genomic sequences identified by MSAP-Seq were methylated, predominantly affecting nuclear genes and intergenic regions, as opposed to repetitive sequences and chloroplast genes. Methylation was found to be more pronounced in the exonic regions of nuclear genes compared to their promoter and intronic regions. The methylated genes were predominantly associated with crucial biological processes such as photosynthesis, ATP synthesis-coupled electron transport, and defence response., Conclusion: This study opens a new research direction in analysing variability in holm oak by evaluating the epigenetic events and mechanisms based on DNA methylation. It sheds light on the enzymatic machinery governing DNA (de)methylation, and the changes in the expression levels of methylases and demethylases in different organs along the developmental stages. The expression level was correlated with the DNA methylation pattern observed, showing the prevalence of de novo methylation and demethylation events in seedlings and embryos, respectively. Several methylated genes involved in the regulation of transposable element silencing, lipid biosynthesis, growth and development, and response to biotic and abiotic stresses are highlighted. MSAP-seq integrated with whole genome bisulphite sequencing and advanced sequencing technologies, such as PacBio or Nanopore, will bring light on epigenetic mechanisms regulating the expression of specific genes and its correlation with the phenotypic variability and the differences in the response to environmental cues, especially those related to climate change., (© 2024. The Author(s).)
- Published
- 2024
- Full Text
- View/download PDF
21. Evolution of a bistable genetic system in fluctuating and nonfluctuating environments.
- Author
-
Fernández-Fernández R, Olivenza DR, Weyer E, Singh A, Casadesús J, and Antonia Sánchez-Romero M
- Subjects
- Epigenesis, Genetic, Operon genetics, Environment, Phenotype, Evolution, Molecular, Biological Evolution, Bacteriophages genetics, Models, Genetic, Mutation, Gene Expression Regulation, Bacterial, Salmonella enterica genetics
- Abstract
Epigenetic mechanisms can generate bacterial lineages capable of spontaneously switching between distinct phenotypes. Currently, mathematical models and simulations propose epigenetic switches as a mechanism of adaptation to deal with fluctuating environments. However, bacterial evolution experiments for testing these predictions are lacking. Here, we exploit an epigenetic switch in Salmonella enterica, the opvAB operon, to show clear evidence that OpvAB bistability persists in changing environments but not in stable conditions. Epigenetic control of transcription in the opvAB operon produces OpvAB
OFF (phage-sensitive) and OpvABON (phage-resistant) cells in a reversible manner and may be interpreted as an example of bet-hedging to preadapt Salmonella populations to the encounter with phages. Our experimental observations and computational simulations illustrate the adaptive value of epigenetic variation as an evolutionary strategy for mutation avoidance in fluctuating environments. In addition, our study provides experimental support to game theory models predicting that phenotypic heterogeneity is advantageous in changing and unpredictable environments., Competing Interests: Competing interests statement:The authors declare no competing interest.- Published
- 2024
- Full Text
- View/download PDF
22. Non-CG DNA hypomethylation promotes photosynthesis and nitrogen fixation in soybean.
- Author
-
Xun H, Wang Y, Yuan J, Lian L, Feng W, Liu S, Hong J, Liu B, Ma J, and Wang X
- Subjects
- Epigenesis, Genetic, Seeds metabolism, Seeds genetics, Seeds growth & development, Plant Proteins genetics, Plant Proteins metabolism, Glycine max genetics, Glycine max metabolism, Glycine max growth & development, DNA Methylation, Photosynthesis genetics, Nitrogen Fixation genetics, Gene Expression Regulation, Plant
- Abstract
Non-CG DNA methylation, a plant-specific epigenetic mark mainly regulated by chromomethylase (CMT), is known to play important roles in Arabidopsis thaliana . However, whether and to what extent non-CG DNA methylation modulates agronomic traits in crops remain to be explored. Here, we describe the consequences of non-CG DNA hypomethylation on development, seed composition, and yield in soybean ( Glycine max ). We created a Gmcmt mutant line lacking function of all four CMT genes. This line exhibited substantial hypomethylation of non-CG (CHG and CHH) sites. Non-CG hypomethylation enhanced chromatin accessibility and promoted or repressed the expression of hundreds of functionally relevant genes, including upregulation of GOLDEN-LIKE 10 ( GmGLK10 ), which led to enhanced photosynthesis and, unexpectedly, improved nitrogen fixation efficiency. The Gmcmt line produced larger seeds with increased protein content. This study provides insights into the mechanisms of non-CG methylation-based epigenetic regulation of soybean development and suggests viable epigenetic strategies for improving soybean yield and nutritional value., Competing Interests: Competing interests statement:The authors declare no competing interest.
- Published
- 2024
- Full Text
- View/download PDF
23. Postprandial cardiac hypertrophy is sustained by mechanics, epigenetic, and metabolic reprogramming in pythons.
- Author
-
Crocini C, Woulfe KC, Ozeroff CD, Perni S, Cardiello J, Walker CJ, Wilson CE, Anseth K, Allen MA, and Leinwand LA
- Subjects
- Animals, Postprandial Period physiology, Energy Metabolism, Myofibrils metabolism, Calcium metabolism, Adaptation, Physiological, Myocardium metabolism, Metabolic Reprogramming, Cardiomegaly metabolism, Cardiomegaly genetics, Cardiomegaly physiopathology, Boidae physiology, Boidae genetics, Epigenesis, Genetic
- Abstract
Constricting pythons, known for their ability to consume infrequent, massive meals, exhibit rapid and reversible cardiac hypertrophy following feeding. Our primary goal was to investigate how python hearts achieve this adaptive response after feeding. Isolated myofibrils increased force after feeding without changes in sarcomere ultrastructure and without increasing energy cost. Ca
2+ transients were prolonged after feeding with no changes in myofibril Ca2+ sensitivity. Feeding reduced titin-based tension, resulting in decreased cardiac tissue stiffness. Feeding also reduced the activity of sirtuins, a metabolically linked class of histone deacetylases, and increased chromatin accessibility. Transcription factor enrichment analysis on transposase-accessible chromatin with sequencing revealed the prominent role of transcription factors Yin Yang1 and NRF1 in postfeeding cardiac adaptation. Gene expression also changed with the enrichment of translation and metabolism. Finally, metabolomics analysis and adenosine triphosphate production demonstrated that cardiac adaptation after feeding not only increased energy demand but also energy production. These findings have broad implications for our understanding of cardiac adaptation across species and hold promise for the development of innovative approaches to address cardiovascular diseases., Competing Interests: Competing interests statement:The authors declare no competing interest.- Published
- 2024
- Full Text
- View/download PDF
24. Oncogenic Enhancers in Leukemia.
- Author
-
Mulet-Lazaro R and Delwel R
- Subjects
- Humans, Oncogenes genetics, Mutation, Epigenesis, Genetic, Animals, Carcinogenesis genetics, Leukemia genetics, Leukemia pathology, Enhancer Elements, Genetic genetics
- Abstract
Although the study of leukemogenesis has traditionally focused on protein-coding genes, the role of enhancer dysregulation is becoming increasingly recognized. The advent of high-throughput sequencing, together with a better understanding of enhancer biology, has revealed how various genetic and epigenetic lesions produce oncogenic enhancers that drive transformation. These aberrations include translocations that lead to enhancer hijacking, point mutations that modulate enhancer activity, and copy number alterations that modify enhancer dosage. In this review, we describe these mechanisms in the context of leukemia and discuss potential therapeutic avenues to target these regulatory elements. Significance: Large-scale sequencing projects have uncovered recurrent gene mutations in leukemia, but the picture remains incomplete: some patients harbor no such aberrations, whereas others carry only a few that are insufficient to bring about transformation on their own. One of the missing pieces is enhancer dysfunction, which only recently has emerged as a critical driver of leukemogenesis. Knowledge of the various mechanisms of enhancer dysregulation is thus key for a complete understanding of leukemia and its causes, as well as the development of targeted therapies in the era of precision medicine., (©2024 American Association for Cancer Research.)
- Published
- 2024
- Full Text
- View/download PDF
25. Pyrimidine-Dependent UV-Mediated Cross-Linking Magnifies Minor Genetic or Epigenetic Changes in Clinical Samples.
- Author
-
Yu F, Ahmed F, Smilkou S, Yasmin-Karim S, Darbeheshti F, Markou A, Bullock M, Boukovinas I, Adalsteinsson VA, Lianidou E, and Makrigiorgos GM
- Subjects
- Humans, Pyrimidines, Proto-Oncogene Proteins B-raf genetics, Mutation, Melanoma genetics, DNA Methylation, Alleles, Thyroid Neoplasms genetics, Polymerase Chain Reaction methods, Ultraviolet Rays, Epigenesis, Genetic
- Abstract
Background: Detection of minor DNA allele alterations is becoming increasingly important for early detection and monitoring of cancer. We describe a new method that uses ultraviolet light to eliminate wild-type DNA alleles and enables improved detection of minor genetic or epigenetic changes., Methods: Pyrimidine-dependent UV-based minor-allele enrichment (PD-UVME) employed oligonucleotide probes that incorporated a UVA-sensitive 3-cyanovinylcarbazole (CNVK), placed directly opposite interrogated pyrimidines, such as thymine (T) or cytosine (C) in wild-type (WT) DNA. Upon UVA-illumination, CNVK cross-linked with T/C, preventing subsequent amplification. Mutations that removed the T/C escaped cross-linking and were amplified and detected. Similarly, CNVK discriminated between methylated and unmethylated cytosine in CpG dinucleotides, enabling direct enrichment of unmethylated DNA targets. PD-UVME was combined with digital droplet PCR (ddPCR) to detect serine/threonine-protein kinase B-Raf (BRAF) V600E mutations in model systems, thyroid patient cancer tissue samples, and circulating DNA of tumor origin (ctDNA) from melanoma patients., Results: One thyroid cancer sample out of 9, and 6 circulating-DNA samples out of 7 were found to be BRAF V600E-positive via PD-UVME while classified as negative by conventional ddPCR. Positive samples via conventional ddPCR were also found positive via PD-UVME. All 10 circulating cell-free DNA (cfDNA) samples obtained from normal volunteers were negative via both approaches. Furthermore, preferential enrichment of unmethylated alleles in MAGEA1 promoters using PD-UVME was demonstrated., Conclusions: PD-UVME mutation/methylation enrichment performed prior to ddPCR magnifies low-level mutations or epigenetic changes and increases sensitivity and confidence in the results. It can assist with clinical decisions that hinge on the presence of trace alterations like BRAF V600E., (© Association for Diagnostics & Laboratory Medicine 2024. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)
- Published
- 2024
- Full Text
- View/download PDF
26. Detecting Small Cell Transformation in Patients with Advanced EGFR Mutant Lung Adenocarcinoma through Epigenomic cfDNA Profiling.
- Author
-
El Zarif T, Meador CB, Qiu X, Seo JH, Davidsohn MP, Savignano H, Lakshminarayanan G, McClure HM, Canniff J, Fortunato B, Li R, Banwait MK, Semaan K, Eid M, Long H, Hung YP, Mahadevan NR, Barbie DA, Oser MG, Piotrowska Z, Choueiri TK, Baca SC, Hata AN, Freedman ML, and Berchuck JE
- Subjects
- Humans, Mice, Animals, Biomarkers, Tumor genetics, Female, Small Cell Lung Carcinoma genetics, Small Cell Lung Carcinoma pathology, Small Cell Lung Carcinoma blood, Small Cell Lung Carcinoma diagnosis, DNA Methylation, Male, Cell Transformation, Neoplastic genetics, Epigenesis, Genetic, ErbB Receptors genetics, Adenocarcinoma of Lung genetics, Adenocarcinoma of Lung pathology, Adenocarcinoma of Lung blood, Adenocarcinoma of Lung diagnosis, Mutation, Lung Neoplasms genetics, Lung Neoplasms pathology, Lung Neoplasms blood, Lung Neoplasms diagnosis, Cell-Free Nucleic Acids genetics, Cell-Free Nucleic Acids blood, Epigenomics methods
- Abstract
Purpose: Histologic transformation to small cell lung cancer (SCLC) is a mechanism of treatment resistance in patients with advanced oncogene-driven lung adenocarcinoma (LUAD) that currently requires histologic review for diagnosis. Herein, we sought to develop an epigenomic cell-free DNA (cfDNA)-based approach to noninvasively detect small cell transformation in patients with EGFR mutant (EGFRm) LUAD., Experimental Design: To characterize the epigenomic landscape of transformed (t)SCLC relative to LUAD and de novo SCLC, we performed chromatin immunoprecipitation sequencing (ChIP-seq) to profile the histone modifications H3K27ac, H3K4me3, and H3K27me3; methylated DNA immunoprecipitation sequencing (MeDIP-seq); assay for transposase-accessible chromatin sequencing; and RNA sequencing on 26 lung cancer patient-derived xenograft (PDX) tumors. We then generated and analyzed H3K27ac ChIP-seq, MeDIP-seq, and whole genome sequencing cfDNA data from 1 mL aliquots of plasma from patients with EGFRm LUAD with or without tSCLC., Results: Analysis of 126 epigenomic libraries from the lung cancer PDXs revealed widespread epigenomic reprogramming between LUAD and tSCLC, with a large number of differential H3K27ac (n = 24,424), DNA methylation (n = 3,298), and chromatin accessibility (n = 16,352) sites between the two histologies. Tumor-informed analysis of each of these three epigenomic features in cfDNA resulted in accurate noninvasive discrimination between patients with EGFRm LUAD versus tSCLC [area under the receiver operating characteristic curve (AUROC) = 0.82-0.87]. A multianalyte cfDNA-based classifier integrating these three epigenomic features discriminated between EGFRm LUAD versus tSCLC with an AUROC of 0.94., Conclusions: These data demonstrate the feasibility of detecting small cell transformation in patients with EGFRm LUAD through epigenomic cfDNA profiling of 1 mL of patient plasma., (©2024 The Authors; Published by the American Association for Cancer Research.)
- Published
- 2024
- Full Text
- View/download PDF
27. Impact of KDM6B mosaic brain knockout on synaptic function and behavior.
- Author
-
Brauer B, Ancatén-González C, Ahumada-Marchant C, Meza RC, Merino-Veliz N, Nardocci G, Varela-Nallar L, Arriagada G, Chávez AE, and Bustos FJ
- Subjects
- Animals, Mice, Brain metabolism, Neuronal Plasticity genetics, Behavior, Animal, Hippocampus metabolism, Epigenesis, Genetic, Male, Synapses metabolism, Jumonji Domain-Containing Histone Demethylases genetics, Jumonji Domain-Containing Histone Demethylases metabolism, Mice, Knockout, Synaptic Transmission genetics, Autism Spectrum Disorder genetics
- Abstract
Autism spectrum disorders (ASD) are complex neurodevelopmental conditions characterized by impairments in social communication, repetitive behaviors, and restricted interests. Epigenetic modifications serve as critical regulators of gene expression playing a crucial role in controlling brain function and behavior. Lysine (K)-specific demethylase 6B (KDM6B), a stress-inducible H3K27me3 demethylase, has emerged as one of the highest ASD risk genes, but the precise effects of KDM6B mutations on neuronal activity and behavioral function remain elusive. Here we show the impact of KDM6B mosaic brain knockout on the manifestation of different autistic-like phenotypes including repetitive behaviors, social interaction, and significant cognitive deficits. Moreover, KDM6B mosaic knockout display abnormalities in hippocampal excitatory synaptic transmission decreasing NMDA receptor mediated synaptic transmission and plasticity. Understanding the intricate interplay between epigenetic modifications and neuronal function may provide novel insights into the pathophysiology of ASD and potentially inform the development of targeted therapeutic interventions., (© 2024. The Author(s).)
- Published
- 2024
- Full Text
- View/download PDF
28. Inhibiting histone deacetylase 6 suppresses the proliferation of microvascular endothelial cells by epigenetically activating miR-375-3p, potentially contributing to bone loss during mechanical unloading.
- Author
-
Xu L, Zhang L, Li G, Zhang X, Sun Q, Hu Z, Cao X, Wang Y, Shi F, and Zhang S
- Subjects
- Animals, Mice, Inbred C57BL, Mice, Coculture Techniques, Cell Differentiation, Male, Bone Resorption pathology, Base Sequence, Histone Deacetylase Inhibitors pharmacology, MicroRNAs metabolism, MicroRNAs genetics, Cell Proliferation, Endothelial Cells metabolism, Histone Deacetylase 6 metabolism, Histone Deacetylase 6 genetics, Microvessels pathology, Hindlimb Suspension, Epigenesis, Genetic, Osteoblasts metabolism
- Abstract
Background: Mechanical unloading-induced bone loss threatens prolonged spaceflight and human health. Recent studies have confirmed that osteoporosis is associated with a significant reduction in bone microvessels, but the relationship between them and the underlying mechanism under mechanical unloading are still unclear., Methods: We established a 2D clinostat and hindlimb-unloaded (HLU) mouse model to simulate unloading in vitro and in vivo. Micro-CT scanning was performed to assess changes in the bone microstructure and mass of the tibia. The levels of CD31, Endomucin (EMCN) and histone deacetylase 6 (HDAC6) in tibial microvessels were detected by immunofluorescence (IF) staining. In addition, we established a coculture system of microvascular endothelial cells (MVECs) and osteoblasts, and qRT‒PCR or western blotting was used to detect RNA and protein expression; cell proliferation was detected by CCK‒8 and EdU assays. ChIP was used to detect whether HDAC6 binds to the miRNA promoter region., Results: Bone mass and bone microvessels were simultaneously significantly reduced in HLU mice. Furthermore, MVECs effectively promoted the proliferation and differentiation of osteoblasts under coculture conditions in vitro. Mechanistically, we found that the HDAC6 content was significantly reduced in the bone microvessels of HLU mice and that HDAC6 inhibited the expression of miR-375-3p by reducing histone acetylation in the miR-375 promoter region in MVECs. miR-375-3p was upregulated under unloading and it could inhibit MVEC proliferation by directly targeting low-density lipoprotein-related receptor 5 (LRP5) expression. In addition, silencing HDAC6 promoted the miR-375-3p/LRP5 pathway to suppress MVEC proliferation under mechanical unloading, and regulation of HDAC6/miR-375-3p axis in MVECs could affect osteoblast proliferation under coculture conditions., Conclusion: Our study revealed that disuse-induced bone loss may be closely related to a reduction in the number of bone microvessels and that the modulation of MVEC function could improve bone loss induced by unloading. Mechanistically, the HDAC6/miR-375-3p/LRP5 pathway in MVECs might be a promising strategy for the clinical treatment of unloading-induced bone loss., (© 2024. The Author(s).)
- Published
- 2024
- Full Text
- View/download PDF
29. Tracking induced pluripotent stem cell differentiation with a fluorescent genetically encoded epigenetic probe.
- Author
-
Stepanov AI, Shuvaeva AA, Putlyaeva LV, Lukyanov DK, Galiakberova AA, Gorbachev DA, Maltsev DI, Pronina V, Dylov DV, Terskikh AV, Lukyanov KA, and Gurskaya NG
- Subjects
- Humans, Neurons metabolism, Neurons cytology, Animals, Mice, Cell Differentiation genetics, Induced Pluripotent Stem Cells metabolism, Induced Pluripotent Stem Cells cytology, Epigenesis, Genetic, Histones metabolism, Histones genetics, Fluorescent Dyes chemistry, Fluorescent Dyes metabolism
- Abstract
Epigenetic modifications (methylation, acetylation, etc.) of core histones play a key role in regulation of gene expression. Thus, the epigenome changes strongly during various biological processes such as cell differentiation and dedifferentiation. Classical methods of analysis of epigenetic modifications such as mass-spectrometry and chromatin immuno-precipitation, work with fixed cells only. Here we present a genetically encoded fluorescent probe, MPP8-Green, for detecting H3K9me3, a histone modification associated with inactive chromatin. This probe, based on the chromodomain of MPP8, allows for visualization of H3K9me3 epigenetic landscapes in single living cells. We used this probe to track changes in H3K9me3 landscapes during the differentiation of induced pluripotent stem cells (iPSCs) into induced neurons. Our findings revealed two major waves of global H3K9me3 reorganization during 4-day differentiation, namely on the first and third days, whereas nearly no changes occurred on the second and fourth days. The proposed method LiveMIEL (Live-cell Microscopic Imaging of Epigenetic Landscapes), which combines genetically encoded epigenetic probes and machine learning approaches, enables classification of multiparametric epigenetic signatures of single cells during stem cell differentiation and potentially in other biological models., (© 2024. The Author(s).)
- Published
- 2024
- Full Text
- View/download PDF
30. Adenosine kinase inhibition protects mice from abdominal aortic aneurysm via epigenetic modulation of VSMC inflammation.
- Author
-
Xu J, Liu Z, Yang Q, Ma Q, Zhou Y, Cai Y, Zhao D, Zhao G, Lu T, Ouyang K, Hong M, Kim HW, Shi H, Zhang J, Fulton D, Miller C, Malhotra R, Weintraub NL, and Huo Y
- Subjects
- Animals, Humans, Cells, Cultured, Male, Adenosine metabolism, Adenosine analogs & derivatives, Signal Transduction, Aortitis prevention & control, Aortitis enzymology, Aortitis pathology, Aortitis metabolism, Aortitis chemically induced, Aortitis genetics, DNA Methylation, Inflammation Mediators metabolism, Mice, Protein Kinase Inhibitors pharmacology, Morpholines, Pyrimidines, Aortic Aneurysm, Abdominal prevention & control, Aortic Aneurysm, Abdominal chemically induced, Aortic Aneurysm, Abdominal pathology, Aortic Aneurysm, Abdominal enzymology, Aortic Aneurysm, Abdominal metabolism, Aortic Aneurysm, Abdominal genetics, Adenosine Kinase genetics, Adenosine Kinase metabolism, Adenosine Kinase antagonists & inhibitors, Muscle, Smooth, Vascular enzymology, Muscle, Smooth, Vascular pathology, Muscle, Smooth, Vascular metabolism, Muscle, Smooth, Vascular drug effects, Epigenesis, Genetic, Disease Models, Animal, Angiotensin II, Myocytes, Smooth Muscle enzymology, Myocytes, Smooth Muscle pathology, Myocytes, Smooth Muscle metabolism, Myocytes, Smooth Muscle drug effects, Mice, Inbred C57BL, Aorta, Abdominal pathology, Aorta, Abdominal metabolism, Aorta, Abdominal enzymology, Calcium Chloride
- Abstract
Aims: Abdominal aortic aneurysm (AAA) is a common, serious vascular disease with no effective pharmacological treatment. The nucleoside adenosine plays an important role in modulating vascular homeostasis, which prompted us to determine whether adenosine kinase (ADK), an adenosine metabolizing enzyme, modulates AAA formation via control of the intracellular adenosine level, and to investigate the underlying mechanisms., Methods and Results: We used a combination of genetic and pharmacological approaches in murine models of AAA induced by calcium chloride (CaCl2) application or angiotensin II (Ang II) infusion to study the role of ADK in the development of AAA. In vitro functional assays were performed by knocking down ADK with adenovirus-short hairpin RNA in human vascular smooth muscle cells (VSMCs), and the molecular mechanisms underlying ADK function were investigated using RNA-sequencing, isotope tracing, and chromatin immunoprecipitation quantitative polymerase chain reaction (ChIP-qPCR). The heterozygous deficiency of ADK protected mice from CaCl2- and Ang II-induced AAA formation. Moreover, specific knockout of ADK in VSMCs prevented Ang II-induced AAA formation, as evidenced by reduced aortic extracellular elastin fragmentation, neovascularization, and aortic inflammation. Mechanistically, ADK knockdown in VSMCs markedly suppressed the expression of inflammatory genes associated with AAA formation, and these effects were independent of adenosine receptors. The metabolic flux and ChIP-qPCR results showed that ADK knockdown in VSMCs decreased S-adenosylmethionine (SAM)-dependent transmethylation, thereby reducing H3K4me3 binding to the promoter regions of the genes that are associated with inflammation, angiogenesis, and extracellular elastin fragmentation. Furthermore, the ADK inhibitor ABT702 protected mice from CaCl2-induced aortic inflammation, extracellular elastin fragmentation, and AAA formation., Conclusion: Our findings reveal a novel role for ADK inhibition in attenuating AAA via epigenetic modulation of key inflammatory genes linked to AAA pathogenesis., Competing Interests: Conflict of interest: none declared., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)
- Published
- 2024
- Full Text
- View/download PDF
31. Multi-omic lineage tracing predicts the transcriptional, epigenetic and genetic determinants of cancer evolution.
- Author
-
Nadalin F, Marzi MJ, Pirra Piscazzi M, Fuentes-Bravo P, Procaccia S, Climent M, Bonetti P, Rubolino C, Giuliani B, Papatheodorou I, Marioni JC, and Nicassio F
- Subjects
- Humans, Animals, Single-Cell Analysis methods, Mice, Cell Lineage genetics, Cell Line, Tumor, Transcription, Genetic, Phenotype, Multiomics, Epigenesis, Genetic, Neoplasms genetics, Gene Expression Regulation, Neoplastic
- Abstract
Cancer is a highly heterogeneous disease, where phenotypically distinct subpopulations coexist and can be primed to different fates. Both genetic and epigenetic factors may drive cancer evolution, however little is known about whether and how such a process is pre-encoded in cancer clones. Using single-cell multi-omic lineage tracing and phenotypic assays, we investigate the predictive features of either tumour initiation or drug tolerance within the same cancer population. Clones primed to tumour initiation in vivo display two distinct transcriptional states at baseline. Remarkably, these states share a distinctive DNA accessibility profile, highlighting an epigenetic basis for tumour initiation. The drug tolerant niche is also largely pre-encoded, but only partially overlaps the tumour-initiating one and evolves following two genetically and transcriptionally distinct trajectories. Our study highlights coexisting genetic, epigenetic and transcriptional determinants of cancer evolution, unravelling the molecular complexity of pre-encoded tumour phenotypes., (© 2024. The Author(s).)
- Published
- 2024
- Full Text
- View/download PDF
32. PIK3CA Mutated Colorectal Cancers Without KRAS, NRAS and BRAF Mutations Possess Common and Potentially Targetable Mutations in Epigenetic Modifiers and DNA Damage Response Genes.
- Author
-
Voutsadakis IA
- Subjects
- Humans, DNA Damage, Female, GTP Phosphohydrolases genetics, Male, Membrane Proteins genetics, Aged, Middle Aged, Colorectal Neoplasms genetics, Colorectal Neoplasms pathology, Class I Phosphatidylinositol 3-Kinases genetics, Mutation, Proto-Oncogene Proteins B-raf genetics, Epigenesis, Genetic, Proto-Oncogene Proteins p21(ras) genetics
- Abstract
Background/aim: Despite therapeutic advancements, metastatic colorectal cancer is usually fatal, necessitating novel approaches based on the molecular pathogenesis to improve outcomes. Some colorectal cancers have no mutations in the extended RAS panel (KRAS, NRAS, BRAF) genes and represent a special subset, which deserves particular therapeutic considerations., Materials and Methods: The genomic landscape of colorectal cancers from publicly available genomic series was interrogated, using the cBioportal platform. Colorectal cancer cohorts with cancers devoid of KRAS/NRAS or BRAF mutations were evaluated for the presence of mutations in the catalytic sub-unit alpha of kinase PI3K, encoded by the gene PIK3CA., Results: PIK3CA mutations in the absence of KRAS/NRAS/BRAF mutations were observed in 3.7% to 7.6% of colorectal cancers in the different series examined. Patients with all four genes in wildtype configuration (quadruple wild type) represented 32.2% to 39.9% of cases in the different series examined. Compared with quadruple wild type cancers, triple (KRAS/NRAS/BRAF) wild type/PIK3CA mutated cancers had a higher prevalence of high TMB cases and additional mutations in colorectal cancer associated genes except for mutations in TP53. Mutations in genes encoding for epigenetic modifiers and the DNA damage response (DDR) were also more frequent in triple wild type/PIK3CA mutated cancers. The prognosis of the two groups was comparable., Conclusion: Colorectal cancers with PIK3CA mutations in the absence of KRAS/NRAS/BRAF mutations have frequently mutations in epigenetic modifiers and DDR response genes, which may provide opportunities for targeting. These mutations are present in a smaller subset of quadruple wild type cancers., (Copyright © 2024, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)
- Published
- 2024
- Full Text
- View/download PDF
33. Approaching the mystery of aging by the epigenetic clock.
- Author
-
Inoue-Murayama M
- Subjects
- Animals, Humans, Aging, Epigenesis, Genetic
- Published
- 2024
- Full Text
- View/download PDF
34. The impact of histone lactylation on the tumor microenvironment and metabolic pathways and its potential in cancer therapy.
- Author
-
Zhou J, Ma X, Liu X, Liu Y, Fu J, Qi Y, and Liu H
- Subjects
- Humans, Animals, Epigenesis, Genetic, DNA Repair, Protein Processing, Post-Translational, Tumor Microenvironment, Neoplasms metabolism, Neoplasms genetics, Neoplasms drug therapy, Neoplasms pathology, Histones metabolism, Metabolic Networks and Pathways
- Abstract
Background: The complexity of cancer is intricately linked to its multifaceted biological processes, including the roles of the tumor microenvironment (TME) as well as genetic and metabolic regulation. Histone lactylation has recently emerged as a novel epigenetic modification mechanism that plays a pivotal role in regulating cancer initiation, proliferation, invasion, and metastasis., Objective: This review aims to elucidate the role of histone lactylation in modulating various aspects of tumor biology, including DNA repair mechanisms, glycolytic metabolic abnormalities, functions of non-tumor cells in the TME, and the promotion of tumor inflammatory responses and immune escape. Additionally, the review explores potential therapeutic strategies targeting histone lactylation., Methods: A comprehensive literature review was performed, analyzing recent findings on histone lactylation and its impact on cancer biology. This involved a systematic examination of studies focusing on biochemical pathways, cellular interactions, and clinical implications related to histone lactylation., Results: Histone lactylation was identified as a critical regulator of tumor cell DNA repair mechanisms and glycolytic metabolic abnormalities. It also significantly influences the functions of non-tumor cells within the TME, promoting tumor inflammatory responses and immune escape. Moreover, histone lactylation acts as a multifunctional biological signaling molecule impacting immune responses within the TME. Various cell types within the TME, including T cells and macrophages, were found to regulate tumor growth and immune escape mechanisms through lactylation., Conclusion: Histone lactylation offers a novel perspective on tumor metabolism and its role in cancer development. It presents promising opportunities for the development of innovative cancer therapies. This review underscores the potential of histone lactylation as a therapeutic target, paving the way for new strategies in cancer treatment., (© 2024. The Author(s) under exclusive licence to The Genetics Society of Korea.)
- Published
- 2024
- Full Text
- View/download PDF
35. SIRT1: a novel regulator in colorectal cancer.
- Author
-
Dong W, Lu J, Li Y, Zeng J, Du X, Yu A, Zhao X, Chi F, Xi Z, and Cao S
- Subjects
- Humans, Animals, Antineoplastic Agents therapeutic use, Antineoplastic Agents pharmacology, Cell Proliferation, Apoptosis, Epigenesis, Genetic, Colorectal Neoplasms pathology, Colorectal Neoplasms genetics, Colorectal Neoplasms metabolism, Colorectal Neoplasms drug therapy, Sirtuin 1 metabolism
- Abstract
The class-III histone deacetylase SIRT1 is the most extensively investigated sirtuin deacetylase. It is resistant to the broad deacetylase inhibitor trichostatin A and depends on oxidized nicotinamide adenine nucleotide (NAD
+ ). SIRT1 plays a crucial role in the tumorigenesis of numerous types of cancers, including colorectal cancer (CRC). Accumulating evidence indicates that SIRT1 is a therapeutic target for CRC; however, the function and underlying mechanism of SIRT1 in CRC still need to be elucidated. Herein, we provide a detailed and updated review to illustrate that SIRT1 regulates many processes that go awry in CRC cells, such as apoptosis, autophagy, proliferation, migration, invasion, metastasis, oxidative stress, resistance to chemo-radio therapy, immune evasion, and metabolic reprogramming. Moreover, we closely link our review to the clinical practice of CRC treatment, summarizing the mechanisms and prospects of SIRT1 inhibitors in CRC therapy. SIRT1 inhibitors as monotherapy in CRC or in combination with chemotherapy, radiotherapy, and immune therapies are comprehensively discussed. From epigenetic regulation to its potential therapeutic effect, we hope to offer novel insights and a comprehensive understanding of SIRT1's role in CRC., Competing Interests: Declaration of Competing Interest All authors disclosed no relevant relationships., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)- Published
- 2024
- Full Text
- View/download PDF
36. Epigenetic modifications of gonadotropin receptors can regulate follicular development.
- Author
-
Yang Y, Feng W, Zhou J, Zhang R, Lin X, Sooranna SR, Deng Y, and Shi D
- Subjects
- Animals, Ovarian Follicle metabolism, Ovarian Follicle physiology, Female, Humans, Receptors, Gonadotropin genetics, Receptors, Gonadotropin metabolism, Receptors, LH genetics, Receptors, LH metabolism, Receptors, FSH genetics, Receptors, FSH metabolism, Epigenesis, Genetic
- Abstract
The spatiotemporal transcription of follicle-stimulating hormone receptor (FSHR) and luteinizing hormone/human chorionic gonadotropin receptor (LHCGR) are crucial events for follicular development. However, their regulatory mechanisms are unclear. DNA methylation and histone acetylation are the main epigenetic modifications, and play important roles in transcriptional expression, which regulate cell responses including cell proliferation, senescence and apoptosis. This review will discuss the dynamic epigenetic modifications of FSHR and LHCGR that occur during the process of follicular development and their response to gonadotropins. In addition, some alteration patterns that occur during these epigenetic modifications, as well as their retrospect retrotransposons, which regulate the gene expression levels of FSHR and LHCGR will be discussed., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)
- Published
- 2024
- Full Text
- View/download PDF
37. Epigenomic differences between osteoarthritis grades in primary cartilage.
- Author
-
Kreitmaier P, Swift D, Wilkinson JM, and Zeggini E
- Subjects
- Humans, Female, Male, Middle Aged, Aged, Epigenomics, Sex Factors, Severity of Illness Index, Cartilage, Articular metabolism, Cartilage, Articular pathology, Osteoarthritis, Knee genetics, Osteoarthritis, Knee metabolism, Osteoarthritis, Knee pathology, DNA Methylation, Epigenesis, Genetic, Chondrocytes metabolism, Chondrocytes pathology, Genome-Wide Association Study
- Abstract
Objective: Osteoarthritis is a common and complex joint disorder that shows higher prevalence and greater disease severity in women. Here, we investigate genome-wide methylation profiles of primary chondrocytes from osteoarthritis patients., Design: We compare genome-wide methylation profiles of macroscopically intact (low-grade) and degraded (high-grade) osteoarthritis cartilage samples matched from osteoarthritis patients undergoing knee replacement surgery. We perform an epigenome-wide association study for cartilage degeneration across 170 patients and separately in 96 women and 74 men., Results: We reveal widespread epigenetic differences with enrichments of nervous system and apoptosis-related processes. We further identify substantial similarities between sexes, but also sex-specific markers and pathways., Conclusions: Together, we provide the largest genome-wide methylation profiles of primary cartilage to date with enhanced and sex-specific insights into epigenetic processes underlying osteoarthritis progression., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)
- Published
- 2024
- Full Text
- View/download PDF
38. The Genome-wide DNA methylation changes in gastrointestinal surgery patients with and without postoperative delirium: Evidence of immune process in its pathophysiology.
- Author
-
Nishizawa Y, Yamanashi T, Nishiguchi T, Kajitani N, Miura A, Matsuo R, Tanio A, Yamamoto M, Sakamoto T, Fujiwara Y, Thompson K, Malicoat J, Yamanishi K, Seki T, Kanazawa T, Iwata M, and Shinozaki G
- Subjects
- Humans, Male, Female, Middle Aged, Aged, Postoperative Complications immunology, Epigenesis, Genetic, Genome-Wide Association Study, DNA Methylation, Delirium blood, Delirium genetics, Delirium physiopathology, Digestive System Surgical Procedures adverse effects
- Abstract
Aim: The pathophysiological mechanisms of postoperative delirium (POD) are still unclear, and there is no reliable biomarker to distinguish between those with and without POD. Our aim was to discover DNAm markers associated with POD in blood collected from patients before and after gastrointestinal surgery., Method: We collected blood samples from 16 patients including 7 POD patients at three timepoints; before surgery (pre), the first and third postoperative days (day1 and day3). We measured differences in DNA methylation between POD and control groups between pre and day1 as well as between pre and day3 using the Illumina EPIC array method. Besides, enrichment analysis with Gene Ontology and Kyoto Encyclopedia of Genes and Genomes terms were also performed after excluding influence of common factors related to surgery and anesthesia., Result: The results showed that pre and day1 comparisons showed that immune and inflammatory signals such as 'T-cell activation' were significantly different, consistent with our previous studies with non-Hispanic White subjects. In contrast, we found that these signals were not significant any more when pre was compared with day3., Conclusion: These results provide strong evidence for the involvement of inflammatory and immune-related epigenetic signals in the pathogenesis of delirium, including POD, regardless of ethnic background. These findings also suggest that DNAm, which is involved in inflammation and immunity, is dynamically altered in patients with POD. In summary, the present results indicate that these signals may serve as a new diagnostic tool for POD., Competing Interests: Declaration of competing interest Gen Shinozaki has pending patents “Epigenetic Biomarker of Delirium Risk” in the PCT Application No. PCT/US19/51276, in the PCT Application No. PCT/US21/63166, and in U.S. Provisional Patent No. 62/731599. All other authors have declared that no conflict of interest exists., (Copyright © 2024 Elsevier Ltd. All rights reserved.)
- Published
- 2024
- Full Text
- View/download PDF
39. Epigenetic editing works like a CHARM.
- Author
-
Minton K
- Subjects
- Humans, CRISPR-Cas Systems, Epigenomics methods, Animals, Epigenesis, Genetic, Gene Editing methods
- Published
- 2024
- Full Text
- View/download PDF
40. Hop stunt viroid infection induces heterochromatin reorganization.
- Author
-
Marquez-Molins J, Cheng J, Corell-Sierra J, Juarez-Gonzalez VT, Villalba-Bermell P, Annacondia ML, Gomez G, and Martinez G
- Subjects
- Cucumis sativus virology, Cucumis sativus genetics, Plant Viruses physiology, Plant Viruses pathogenicity, DNA Transposable Elements genetics, Host-Pathogen Interactions genetics, Heterochromatin metabolism, Heterochromatin genetics, Viroids genetics, Viroids physiology, Viroids pathogenicity, Histones metabolism, Plant Diseases virology, Plant Diseases genetics, Epigenesis, Genetic, Gene Expression Regulation, Plant
- Abstract
Viroids are pathogenic noncoding RNAs that completely rely on their host molecular machinery to accomplish their life cycle. Several interactions between viroids and their host molecular machinery have been identified, including interference with epigenetic mechanisms such as DNA methylation. Despite this, whether viroids influence changes in other epigenetic marks such as histone modifications remained unknown. Epigenetic regulation is particularly important during pathogenesis processes because it might be a key regulator of the dynamism of the defense response. Here we have analyzed the changes taking place in Cucumis sativus (cucumber) facultative and constitutive heterochromatin during hop stunt viroid (HSVd) infection using chromatin immunoprecipitation (ChIP) of the two main heterochromatic marks: H3K9me2 and H3K27me3. We find that HSVd infection is associated with changes in both H3K27me3 and H3K9me2, with a tendency to decrease the levels of repressive epigenetic marks through infection progression. These epigenetic changes are connected to the transcriptional regulation of their expected targets, genes, and transposable elements. Indeed, several genes related to the defense response are targets of both epigenetic marks. Our results highlight another host regulatory mechanism affected by viroid infection, providing further information about the complexity of the multiple layers of interactions between pathogens/viroids and hosts/plants., (© 2024 The Author(s). New Phytologist © 2024 New Phytologist Foundation.)
- Published
- 2024
- Full Text
- View/download PDF
41. Causal benefits of 25 dietary intakes on epigenetic ageing: a Mendelian randomisation study.
- Author
-
Ding K, Jiang W, Wuke S, and Lei M
- Subjects
- Humans, Cross-Sectional Studies, Mendelian Randomization Analysis, Epigenesis, Genetic, Diet, DNA Methylation, Aging
- Abstract
DNA methylation GrimAge acceleration (DMGA) and intrinsic epigenetic age acceleration (IEAA) are important physiological markers for assessing the ageing process. Evidence from cross-sectional studies suggests that some dietary intake is associated with DMGA and IEAA. However, the causal relationship between them has yet to be elucidated. This Mendelian randomisation study uses genetic variants associated with different dietary intakes as instrumental variables to explore the causal benefits of multiple dietary intakes on DMGA and IEAA. Cheese intake, dark chocolate intake, average weekly red wine intake, dried fruit intake, fresh fruit intake, porridge intake, cereal intake, and liver intake had a negative causal association with DMGA, and poultry intake and doughnut intake had a positive causal association with DMGA ( p < 0.05). Muesli and bran cereal intake had a negative causal association with IEAA, and pineapple intake had a positive causal association with IEAA ( p < 0.05). Dietary intake positively causally associated with IEAA or DMGA may have accelerated biological ageing; conversely, dietary intake negatively causally associated with IEAA or DMGA may have contributed to delaying biological ageing. Based on genetic evidence, this study demonstrated some significant causal benefits of dietary intake on DMGA and IEAA, suggesting the possibility of intervening in DNA methylation acceleration and epigenetic age acceleration by adjusting these food intakes, thereby promoting health and delaying ageing. However, the findings of this study are exploratory and preliminary and need to be supported and validated by evidence from further clinical studies and mechanistic studies.
- Published
- 2024
- Full Text
- View/download PDF
42. Unravelling the impact of RNA methylation genetic and epigenetic machinery in the treatment of cardiomyopathy.
- Author
-
Liu L, Yu L, Wang Y, Zhou L, Liu Y, Pan X, and Huang J
- Subjects
- Humans, Animals, Methylation, RNA Methylation, Epigenesis, Genetic, Cardiomyopathies genetics, Cardiomyopathies metabolism, Cardiomyopathies therapy, RNA genetics, RNA metabolism
- Abstract
Cardiomyopathy (CM) represents a heterogeneous group of diseases primarily affecting cardiac structure and function, with genetic and epigenetic dysregulation playing a pivotal role in its pathogenesis. Emerging evidence from the burgeoning field of epitranscriptomics has brought to light the significant impact of various RNA modifications, notably N6-methyladenosine (m6A), 5-methylcytosine (m5C), N7-methylguanosine (m7G), N1-methyladenosine (m1A), 2'-O-methylation (Nm), and 6,2'-O-dimethyladenosine (m6Am), on cardiomyocyte function and the broader processes of cardiac and vascular remodelling. These modifications have been shown to influence key pathological mechanisms including mitochondrial dysfunction, oxidative stress, cardiomyocyte apoptosis, inflammation, immune response, and myocardial fibrosis. Importantly, aberrations in the RNA methylation machinery have been observed in human CM cases and animal models, highlighting the critical role of RNA methylating enzymes and their potential as therapeutic targets or biomarkers for CM. This review underscores the necessity for a deeper understanding of RNA methylation processes in the context of CM, to illuminate novel therapeutic avenues and diagnostic tools, thereby addressing a significant gap in the current management strategies for this complex disease., Competing Interests: Declaration of Competing Interest The authors have no relevant financial or nonfinancial interests to disclose., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)
- Published
- 2024
- Full Text
- View/download PDF
43. Inhibition of Renin Expression Is Regulated by an Epigenetic Switch From an Active to a Poised State.
- Author
-
Smith JP, Paxton R, Medrano S, Sheffield NC, Sequeira-Lopez MLS, and Gomez RA
- Subjects
- Animals, Mice, Gene Expression Regulation, Juxtaglomerular Apparatus metabolism, p300-CBP Transcription Factors metabolism, p300-CBP Transcription Factors genetics, Bromodomain Containing Proteins, Nuclear Proteins, Epigenesis, Genetic, Renin metabolism, Renin genetics, Transcription Factors genetics, Transcription Factors metabolism
- Abstract
Background: Renin-expressing cells are myoendocrine cells crucial for the maintenance of homeostasis. Renin is regulated by cAMP, p300 (histone acetyltransferase p300)/CBP (CREB-binding protein), and Brd4 (bromodomain-containing protein 4) proteins and associated pathways. However, the specific regulatory changes that occur following inhibition of these pathways are not clear., Methods: We treated As4.1 cells (tumoral cells derived from mouse juxtaglomerular cells that constitutively express renin) with 3 inhibitors that target different factors required for renin transcription: H-89-dihydrochloride, PKA (protein kinase A) inhibitor; JQ1, Brd4 bromodomain inhibitor; and A-485, p300/CBP inhibitor. We performed assay for transposase-accessible chromatin with sequencing (ATAC-seq), single-cell RNA sequencing, cleavage under targets and tagmentation (CUT&Tag), and chromatin immunoprecipitation sequencing for H3K27ac (acetylation of lysine 27 of the histone H3 protein) and p300 binding on biological replicates of treated and control As4.1 cells., Results: In response to each inhibitor, Ren1 expression was significantly reduced and reversible upon washout. Chromatin accessibility at the Ren1 locus did not markedly change but was globally reduced at distal elements. Inhibition of PKA led to significant reductions in H3K27ac and p300 binding specifically within the Ren1 super-enhancer region. Further, we identified enriched TF (transcription factor) motifs shared across each inhibitory treatment. Finally, we identified a set of 9 genes with putative roles across each of the 3 renin regulatory pathways and observed that each displayed differentially accessible chromatin, gene expression, H3K27ac, and p300 binding at their respective loci., Conclusions: Inhibition of renin expression in cells that constitutively synthesize and release renin is regulated by an epigenetic switch from an active to poised state associated with decreased cell-cell communication and an epithelial-mesenchymal transition. This work highlights and helps define the factors necessary for renin cells to alternate between myoendocrine and contractile phenotypes., Competing Interests: None.
- Published
- 2024
- Full Text
- View/download PDF
44. Epigenetic modulation of cytokine expression in Mycobacterium tuberculosis-infected monocyte derived-dendritic cells: Implications for tuberculosis diagnosis.
- Author
-
Meskini M, Zamani MS, Amanzadeh A, Bouzari S, Karimipoor M, Fuso A, Fateh A, and Siadat SD
- Subjects
- Humans, Tumor Necrosis Factor-alpha metabolism, Interleukin-10 metabolism, Interleukin-10 genetics, Mycobacterium tuberculosis immunology, Epigenesis, Genetic, DNA Methylation, Cytokines metabolism, Dendritic Cells metabolism, Monocytes metabolism, Tuberculosis microbiology, Tuberculosis genetics, Tuberculosis immunology, Tuberculosis metabolism
- Abstract
Background: To delineate alterations in DNA methylation at high resolution within the genomic profile of monocyte-derived-dendritic cells (mo-DCs) in connection with Mycobacterium tuberculosis (MTB) infection, with particular emphasis on pro/ anti-inflammatory genes., Methods: In the context of this investigation, mo-DCs were infected by various active strains of MTB (Rifampicin-resistant [RIFR], H37Rv, multidrug-resistant [MDR], and extensively drug-resistant [XDR]). Subsequently, the pro/anti-inflammatory hub gene expression levels within the IL-6, IL-12, IFN-γ, IL-1β, TNF-α, and IL-10 pathways were evaluated employing real-time reverse transcription-polymerase chain reaction (RT-PCR). Additionally, the effects of MTB infection on mo-DC protein expression were examined through western blot analysis. The methylation status (%) of TNF-α and IL-10 was considered through Methylation Sensitive-High Resolution Melting (MS-HRM)., Results: The results revealed an up-regulation of all pro-inflammatory genes among all groups, with TNF-α exhibiting the highest expression level. Conversely, the anti-inflammatory gene (IL-10) showed a down-regulated expression level. Furthermore, the DNA methylation status (%) of TNF-α decreased significantly among all the groups (P < 0.001), although there were no notable distinctions in the DNA methylation status (%) of IL-10 when compared to the control group (P > 0.05)., Conclusion: MTB infection induces DNA methylation changes in mo-DCs. The hypo-methylation of TNF-α may induce the up-regulation of this gene. This correlation revealed that the more resistant the MTB strain (XDR) is, the lower the methylation status (%) in the TNF-α gene., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)
- Published
- 2024
- Full Text
- View/download PDF
45. Epigenetic programming of chicken germ cells: a comparative review.
- Author
-
Woo SJ and Han JY
- Subjects
- Animals, Chick Embryo, DNA Methylation, Mice, Epigenesis, Genetic, Chickens genetics, Germ Cells physiology
- Abstract
Chicken embryos serve as an important model for investigating germ cells due to their ease of accessibility and manipulation within the egg. Understanding the development of germ cells is particularly crucial, as they are the only cell types capable of transmitting genetic information to the next generation. Therefore, gene expression regulation in germ cells is important for genomic function. Epigenetic programming is a crucial biological process for the regulation of gene expression without altering the genome sequence. Although epigenetic programming is evolutionarily conserved, several differences between chickens and mammals have been revealed. In this review, we compared the epigenetic regulation of germ cells in chickens and mammals (mainly mice as a representative species). In mammals, migrating primordial germ cells (precursors for germ cells [PGCs]) undergo global DNA demethylation and persist until sexual differentiation, while in chickens, DNA is demethylated until reaching the gonad but remethylated when sexually differentiated. Prospermatogonia is methylated at the onset of mitotic arrest in mammals, while DNA is demethylated at mitotic arrest in chickens. Furthermore, genomic imprinting and inactivation of sex chromosomes are differentially regulated through DNA methylation in chickens and mammals. Chickens and mammals exhibit different patterns of histone modifications during germ cell development, and non-coding RNA, which is not involved in PGC differentiation in mice, plays an important role in chicken PGC development. Additionally, several chicken-specific non-coding RNAs have been identified. In conclusion, we summarized current knowledge of epigenetic gene regulation of chicken germ cells, comparing that of mammals, and highlighted notable differences between them., Competing Interests: DISCLOSURES The authors declare no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2024
- Full Text
- View/download PDF
46. lncRNAs and epigenetics regulate plant's resilience against biotic stresses.
- Author
-
Yajnik KN, Singh IK, and Singh A
- Subjects
- Plants genetics, Plants metabolism, Gene Expression Regulation, Plant, RNA, Plant genetics, DNA Methylation, Epigenesis, Genetic, RNA, Long Noncoding genetics, Stress, Physiological genetics
- Abstract
With the advent of transcriptomic techniques involving single-stranded RNA sequencing and chromatin isolation by RNA purification-based sequencing, transcriptomic studies of coding and non-coding RNAs have been executed efficiently. These studies acknowledged the role of non-coding RNAs in modulating gene expression. Long non-coding RNAs (lncRNAs) are a kind of non-coding RNAs having lengths of >200 nucleotides, playing numerous roles in plant developmental processes such as photomorphogenesis, epigenetic changes, reproductive tissue development, and in regulating biotic and abiotic stresses. Epigenetic changes further control gene expression by changing their state to "ON-OFF" and also regulate stress memory and its transgenerational inheritance. With well-established regulatory mechanisms, they act as guides, scaffolds, signals, and decoys to modulate gene expression. They act as a major operator of post-transcriptional modifications such as histone and epigenetic modifications, and DNA methylations. The review elaborates on the roles of lncRNAs in plant immunity and also discusses how epigenetic markers alter gene expression in response to pest/pathogen attack and influences chromatin-associated stress memory as well as transgenerational inheritance of epigenetic imprints in plants. The review further summarizes some research studies on how histone modifications and DNA methylations resist pathogenic and pest attacks by activating defense-related genes., Competing Interests: Declaration of competing interest The authors declare that they have no competing/financial/any other interests., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)
- Published
- 2024
- Full Text
- View/download PDF
47. Comprehensive analysis of distinct circadian clock subtypes of adult diffuse glioma and their associations with clinicopathological, genetic, and epigenetic profiles.
- Author
-
Le MK, Tran NQV, Nguyen PT, Nguyen TA, Nakao A, and Kondo T
- Subjects
- Humans, Female, Male, Adult, Middle Aged, Gene Expression Regulation, Neoplastic genetics, Aged, Cohort Studies, Glioma genetics, Glioma pathology, Glioma metabolism, Brain Neoplasms genetics, Brain Neoplasms pathology, Circadian Clocks genetics, Epigenesis, Genetic
- Abstract
The circadian clock (CC) has biological and clinical implications in gliomas. Most studies focused on CC effects on the tumor microenvironment and the application of chronotherapy. The present study focused on CC gene expression patterns and intracellular oncogenic activities. Glioma gene expression data were collected from The Human Cancer Genome Atlas (TCGA) project. After applying inclusion and exclusion criteria, we selected 666 patients from TCGA-GBM and TCGA-LGG projects and included important clinicopathological variables. The entire cohort was subjected to clustering analysis and divided into CC1 and CC2 subtypes based on statistical, biological, and clinical criteria. CC2 gliomas showed higher expression of BMAL1 and CRY1 and lower expression of CRY2 and PER2 (adjusted P < .001). CC2 gliomas had q higher activity of cell proliferation, metabolic reprogramming, angiogenesis, hypoxia, and many oncogenic signals (P < .001). The CC2 subtype contained a higher proportion of glioblastomas (P < .001) and had a worse prognosis (P < .001). Stratified Kaplan-Meier and multivariable Cox analyses illustrated that the CC subtype is an independent prognostic factor to clinicopathological characteristics (P < .001), genetic aberrations (P = .006), and biological processes (P < .001). Thus, this study shows statistical evidence of CC subtypes and their biological, and clinicopathological significance in adult gliomas., (© The Author(s) 2024. Published by Oxford University Press on behalf of American Association of Neuropathologists, Inc. All rights reserved. For permissions, please email: journals.permissions@oup.com.)
- Published
- 2024
- Full Text
- View/download PDF
48. Sex-specific modulation of renal epigenetic and injury markers in aging kidney.
- Author
-
Adams-Sherrod GA, Brooks HL, and Kumar P
- Subjects
- Animals, Female, Male, Sex Factors, Mice, Inbred C57BL, Histones metabolism, Age Factors, Hepatitis A Virus Cellular Receptor 1 metabolism, Hepatitis A Virus Cellular Receptor 1 genetics, Mice, Histone Acetyltransferases metabolism, Histone Acetyltransferases genetics, Sex Characteristics, Kidney metabolism, Epigenesis, Genetic, Aging metabolism, Biomarkers metabolism, Biomarkers blood
- Abstract
Sex differences in renal physiology and pathophysiology are now well established in rodent models and in humans. Epigenetic programming is known to be a critical component of renal injury, as studied mainly in male rodent models; however, not much is known about the impact of biological sex and age on the kidney epigenome. We sought to determine the influence of biological sex and age on renal epigenetic and injury markers, using male and female mice at 4 mo (4M; young), 12 mo (12M), and 24 mo (24M; aged) of age. Females had a significant increase in kidney and body weights and serum creatinine levels and a decrease in serum albumin levels from 4M to 24M of age, whereas minor changes were observed in male mice. Kidney injury molecule-1 levels in serum and renal tissue greatly enhanced from 12M to 24M in both males and females. Circulating histone 3 (H3; damage-associated molecular pattern molecules) levels extensively increased with age; however, males had higher levels than females. Overall, females had markedly high histone acetyltransferase (HAT) activity than age-matched males. Aged mice had decreased HAT activity and increased histone deacetylase activity than sex-matched 12M mice. Aged females had substantially decreased renal H3 methylation at lysine 9 and 27 and histone methyltransferase (HMT) activity than aged male mice. Antiaging protein Klotho levels were significantly higher in young males than age-matched females and decreased substantially with age in males, whereas epigenetic repressor of Klotho, trimethylated H3K27, and its HMT enzyme, enhancer of zeste homolog 2, increased consistently with age in both sexes. Moreover, nuclear translocation and activity of proinflammatory transcription factor nuclear factor-κB (p65) were significantly higher in aged mice. Taken together, our data suggest that renal aging lies in a range between normal and diseased kidneys but may differ between female and male mice, highlighting sex-related differences in the aging process. NEW & NOTEWORTHY Although there is evidence of sex-specific differences in kidney diseases, most preclinical studies have used male rodent models. The clinical data on renal injury have typically not been stratified by sex. Our findings provide convincing evidence of sex-specific differences in age-regulated epigenetic alterations and renal injury markers. This study highlights the importance of including both sexes for better realization of underlying sex differences in signaling mechanisms of aging-related renal pathophysiology.
- Published
- 2024
- Full Text
- View/download PDF
49. Update: the role of epigenetics in the metabolic memory of diabetic complications.
- Author
-
Chen Z, Malek V, and Natarajan R
- Subjects
- Humans, Animals, Diabetes Complications metabolism, Diabetes Complications genetics, Epigenesis, Genetic, DNA Methylation, Diabetic Nephropathies genetics, Diabetic Nephropathies metabolism
- Abstract
Diabetes, a chronic disease characterized by hyperglycemia, is associated with significantly accelerated complications, including diabetic kidney disease (DKD), which increases morbidity and mortality. Hyperglycemia and other diabetes-related environmental factors such as overnutrition, sedentary lifestyles, and hyperlipidemia can induce epigenetic changes. Working alone or with genetic factors, these epigenetic changes that occur without alterations in the underlying DNA sequence, can alter the expression of pathophysiological genes and impair functions of associated target cells/organs, leading to diabetic complications like DKD. Notably, some hyperglycemia-induced epigenetic changes persist in target cells/tissues even after glucose normalization, leading to sustained complications despite glycemic control, so-called metabolic memory. Emerging evidence from in vitro and in vivo animal models and clinical trials with subjects with diabetes identified clear associations between metabolic memory and epigenetic changes including DNA methylation, histone modifications, chromatin structure, and noncoding RNAs at key loci. Targeting such persistent epigenetic changes and/or molecules regulated by them can serve as valuable opportunities to attenuate, or erase metabolic memory, which is crucial to prevent complication progression. Here, we review these cell/tissue-specific epigenetic changes identified to-date as related to diabetic complications, especially DKD, and the current status on targeting epigenetics to tackle metabolic memory. We also discuss limitations in current studies, including the need for more (epi)genome-wide studies, integrative analysis using multiple epigenetic marks and Omics datasets, and mechanistic evaluation of metabolic memory. Considering the tremendous technological advances in epigenomics, genetics, sequencing, and availability of genomic datasets from clinical cohorts, this field is likely to see considerable progress in the upcoming years.
- Published
- 2024
- Full Text
- View/download PDF
50. Research progress of DNA methylation in colorectal cancer (Review).
- Author
-
Wang Y, Wang C, Zhong R, Wang L, and Sun L
- Subjects
- Humans, Biomarkers, Tumor genetics, Gene Expression Regulation, Neoplastic, Animals, DNA Methylation, Colorectal Neoplasms genetics, Colorectal Neoplasms metabolism, Colorectal Neoplasms pathology, Epigenesis, Genetic
- Abstract
DNA methylation is one of the earliest and most significant epigenetic mechanisms discovered. DNA methylation refers, in general, to the addition of a methyl group to a specific base in the DNA sequence under the catalysis of DNA methyltransferase, with S‑adenosine methionine as the methyl donor, via covalent bonding and chemical modifications. DNA methylation is an important factor in inducing cancer. There are different types of DNA methylation, and methylation at different sites plays different roles. It is well known that the progression of colorectal cancer (CRC) is affected by the methylation of key genes. The present review did not only discuss the potential relationship between DNA methylation and CRC but also discussed how DNA methylation affects the development of CRC by affecting key genes. Furthermore, the clinical significance of DNA methylation in CRC was highlighted, including that of the therapeutic targets and biomarkers of methylation; and the importance of DNA methylation inhibitors was discussed as a novel strategy for treatment of CRC. The present review did not only focus upon the latest research findings, but earlier reviews were also cited as references to older literature.
- Published
- 2024
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.