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Epigenetic regulation is a pivotal factor during neuroblastoma (NB) pathogenesis and investigations into cancer epigenetics are actively underway to identify novel therapeutic strategies for NB patients. SUV39H1, a member of the H3K9 methyltransferase family, contributing to tumorigenesis across multiple malignancies. However, its specific role in NB remains unexplored. In this study, we conducted a high-throughput screen utilizing a compound library containing 288 epigenetic drugs, leading to the identification of chaetocin as the most potent NB inhibitor by targeting SUV39H1. Genetic manipulation and therapeutic inhibition of SUV39H1 significantly impacted proliferation, migration, cell cycle phases, and apoptosis in NB cells. Concurrently, chaetocin demonstrated robust anti-tumor efficacy in vivo with tolerable toxicity. RNA-seq unveiled that SUV39H1 knockdown and inhibition down-regulated cell cycle pathways, impacting vital genes such as AURKA. Besides, MCPIP1 emerged as a novel tumor suppressor following SUV39H1 inhibition, which decreased AURKA expression in NB. In detail, SUV39H1 mediated the enrichment of H3K9me3 at the promoter region of MCPIP1, repressing the MCPIP1-mediated degradation of AURKA and facilitating the subsequent accumulation of AURKA, which revealed the oncogenic role of SUV39H1 via the SUV39H1-MCPIP1-AURKA signaling axis in NB. Therapeutic inhibition of SUV39H1 using chaetocin emerges as an effective and safe strategy for NB patients. Illustration of the oncogenic pathway regulated by SUV39H1 in NB., (© 2024. The Author(s).)

The causative mechanisms underlying the genetic relationships of neurodegenerative diseases with epigenetic aging and human longevity remain obscure. We aimed to detect causal associations and shared genetic etiology of neurodegenerative diseases with epigenetic aging and human longevity. We obtained large-scale genome-wide association study summary statistics data for four measures of epigenetic age (GrimAge, PhenoAge, IEAA, and HannumAge) (N = 34,710), multivariate longevity (healthspan, lifespan, and exceptional longevity) (N = 1,349,462), and for multiple neurodegenerative diseases (N = 6618-482,730), including Lewy body dementia, Alzheimer's disease (AD), Parkinson's disease, amyotrophic lateral sclerosis, and multiple sclerosis. Main analyses were conducted using multiplicative random effects inverse-variance weighted Mendelian randomization (MR), and conditional/conjunctional false discovery rate (cond/conjFDR) approach. Shared genomic loci were functionally characterized to gain biological understanding. Evidence showed that AD patients had 0.309 year less in exceptional longevity (IVW beta = -0.309, 95% CI: -0.38 to -0.24, p = 1.51E-19). We also observed suggestively significant causal evidence between AD and GrimAge age acceleration (IVW beta = -0.10, 95% CI: -0.188 to -0.013, p = 0.02). Following the discovery of polygenic overlap, we identified rs78143120 as shared genomic locus between AD and GrimAge age acceleration, and rs12691088 between AD and exceptional longevity. Among these loci, rs78143120 was novel for AD. In conclusion, we observed that only AD had causal effects on epigenetic aging and human longevity, while other neurodegenerative diseases did not. The genetic overlap between them, with mixed effect directions, suggested complex shared genetic etiology and molecular mechanisms., (© 2024 The Author(s). Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.)

Hepatocellular carcinoma (HCC) is a highly malignant tumor with significant global health implications. The role of CD4 + T cells, particularly conventional CD4 + T cells (Tconvs), in HCC progression remains unexplored. Furthermore, epigenetic factors are crucial in immune regulation, yet their specific role in HCC-infiltrating Tconv cells remains elusive. This study elucidates the role of MATR3, an epigenetic regulator, in modulating Tconv activity and immune evasion within the HCC microenvironment. Reanalysis of the scRNA-seq data revealed that early activation of CD4 + T cells is crucial for establishing an antitumor immune response. In vivo and in vitro experiments revealed that Tconv enhances cDC1-induced CD8 + T-cell activation. Screening identified MATR3 as a critical regulator of Tconv function, which is necessary for antitumour activity but harmful when overexpressed. Excessive MATR3 expression exacerbates Tconv exhaustion and impairs function by recruiting the SWI/SNF complex to relax chromatin in the TOX promoter region, leading to aberrant transcriptional changes. In summary, MATR3 is an HCC-specific epigenetic checkpoint that bidirectionally regulates Tconv antitumour immunity, suggesting new therapeutic strategies targeting epigenetic regulators to enhance antitumour immunity in HCC., (© 2024. The Author(s), under exclusive licence to CSI and USTC.)

Diabetic kidney disease (DKD) is the leading cause of chronic kidney disease and end‑stage renal disease, and is characterized by persistent proteinuria and decreased glomerular filtration rate. Despite extensive efforts, the increasing incidence highlights the urgent need for more effective treatments. Histone methylation is a crucial epigenetic modification, and its alteration can destabilize chromatin structure, thereby regulating the transcriptional activity of specific genes. Histone methylation serves a substantial role in the onset and progression of various diseases. In patients with DKD, changes in histone methylation are pivotal in mediating the interactions between genetic and environmental factors. Targeting these modifications shows promise in ameliorating renal histological manifestations, tissue fibrosis and proteinuria, and represents a novel therapeutic frontier with the potential to halt DKD progression. The present review focuses on the alterations in histone methylation during the development of DKD, systematically summarizes its impact on various renal parenchymal cells and underscores the potential of targeted histone methylation modifications in improving DKD outcomes.

Eosinophilic esophagitis (EoE) is a chronic, allergic inflammatory disease of the esophagus characterized by eosinophil accumulation and has a growing global prevalence. EoE significantly impairs quality of life and poses a substantial burden on healthcare resources. Currently, only two FDA-approved medications exist for EoE, highlighting the need for broader research into its management and prevention. Recent advancements in omics technologies, such as genomics, epigenetics, transcriptomics, proteomics, and others, offer new insights into the genetic and immunologic mechanisms underlying EoE. Genomic studies have identified genetic loci and mutations associated with EoE, revealing predispositions that vary by ancestry and indicating EoE's complex genetic basis. Epigenetic studies have uncovered changes in DNA methylation and chromatin structure that affect gene expression, influencing EoE pathology. Transcriptomic analyses have revealed a distinct gene expression profile in EoE, dominated by genes involved in activated type 2 immunity and epithelial barrier function. Proteomic approaches have furthered the understanding of EoE mechanisms, identifying potential new biomarkers and therapeutic targets. However, challenges in integrating diverse omics data persist, largely due to their complexity and the need for advanced computational methods. Machine learning is emerging as a valuable tool for analyzing extensive and intricate datasets, potentially revealing new aspects of EoE pathogenesis. The integration of multi-omics data through sophisticated computational approaches promises significant advancements in our understanding of EoE, improving diagnostics, and enhancing treatment effectiveness. This review synthesizes current omics research and explores future directions for comprehensively understanding the disease mechanisms in EoE., (© 2024. The Author(s).)

Severe acute pancreatitis (SAP) is characterized by acute inflammation of the pancreas. The transcription factor BTB and CNC homology 1 (BACH1) has been implicated in various biological processes, including oxidative stress, apoptosis, and cell cycle regulation. However, its involvement in the pathogenesis of SAP remains relatively understudied. In the present work, our data demonstrated that BACH1 level was significantly increased in SAP patients, cellular, and animal models, while heat shock protein B1 (HSPB1) expression was weakened. Mechanistic assays validated that BACH1 acted as a transcriptional inhibitor of HSPB1. Moreover, HPDE6-C7 cells were stimulated with cerulein (Cer) and LPS to mimic the pathological stages of SAP in vitro. Depletion of BACH1 remarkably improved cell survival and alleviated the oxidative stress, ferroptosis, and inflammatory responses in SAP cell models. However, these changes were dramatically reversed upon co-inhibition of HSPB1. Animal findings confirmed that loss of BACH1 decreased pancreatic injury, inflammatory responses, and ferroptosis, but these effects were weakened by HSPB1 silence. Overall, these findings elucidate that the overexpression of BACH1 favors the ferroptosis and inflammation by transcriptionally inhibiting HSBP1, thereby exacerbating SAP progression., (© 2024 Wiley Periodicals LLC.)

Emerging evidence indicates that metabolism not only is a source of energy and biomaterials for cell division but also acts as a driver of cancer cell plasticity and treatment resistance. This is because metabolic changes lead to remodeling of chromatin and reprogramming of gene expression patterns, furthering tumor cell phenotypic transitions. Therefore, the crosstalk between metabolism and epigenetics seems to hold immense potential for the discovery of novel therapeutic targets for various aggressive tumors. Here, we highlight recent discoveries supporting the concept that the cooperation between metabolism and epigenetics enables cancer to overcome mounting treatment-induced pressures. We discuss how specific metabolites contribute to cancer cell resilience and provide perspective on how simultaneously targeting these key forces could produce synergistic therapeutic effects to improve treatment outcomes., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Nuclear Bcl-xL is found to promote cancer metastasis independently of its mitochondria-based anti-apoptotic activity. How Bcl-xL is translocated into the nucleus and how nuclear Bcl-xL regulates histone H3 trimethyl Lys4 (H3K4me3) modification have yet to be understood. Here, we report that C-terminal Binding Protein 2 (CtBP2) binds to Bcl-xL via its N-terminus and translocates Bcl-xL into the nucleus. Knockdown of CtBP2 by shRNA decreases the nuclear portion of Bcl-xL and reverses Bcl-xL-induced invasion and metastasis in mouse models. Furthermore, knockout of CtBP2 not only reduces the nuclear portion of Bcl-xL but also suppresses Bcl-xL transcription. The binding between Bcl-xL and CtBP2 is required for their interaction with MLL1, a histone H3K4 methyltransferase. Pharmacologic inhibition of the MLL1 enzymatic activity reverses Bcl-xL-induced H3K4me3 and TGFβ mRNA upregulation, as well as invasion. Moreover, the cleavage under targets and release using nuclease (CUT&RUN) assay coupled with next-generation sequencing reveals that H3K4me3 modifications are particularly enriched in the promotor regions of genes encoding TGFβ and its signaling pathway members in cancer cells overexpressing Bcl-xL. Altogether, the metastatic function of Bcl-xL is mediated by its interaction with CtBP2 and MLL1 and this study offers new therapeutic strategies to treat Bcl-xL-overexpressing cancer., Competing Interests: Declaration of competing interest The authors declare no competing financial interests., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Since the mid-1970s, increasingly innovative methods to detect DNA methylation provided detailed information about its distribution, functions, and dynamics. As a result, new concepts were formulated and older ones were revised, transforming our understanding of the associated biology and catalyzing unprecedented advances in biomedical research, drug development, anthropology, and evolutionary biology. In this review, we discuss a few of the most notable advances, which are intimately intertwined with the study of DNA methylation, with a particular emphasis on the past three decades. Examples of these strides include elucidating the intricacies of 5-methylcytosine (5-mC) oxidation, which are at the core of the reversibility of this epigenetic modification; the three-dimensional structural characterization of eukaryotic DNA methyltransferases, which offered insights into the mechanisms that explain several disease-associated mutations; a more in-depth understanding of DNA methylation in development and disease; the possibility to learn about the biology of extinct species; the development of epigenetic clocks and their use to interrogate aging and disease; and the emergence of epigenetic biomarkers and therapies.

The process of aging is a notable risk factor for numerous age-related illnesses. Hence, a reliable technique for evaluating biological age or the pace of aging is crucial for understanding the aging process and its influence on the progression of disease. Epigenetic alterations are recognized as a prominent biomarker of aging, and epigenetic clocks formulated on this basis have been shown to provide precise estimations of chronological age. Extensive research has validated the effectiveness of epigenetic clocks in determining aging rates, identifying risk factors for aging, evaluating the impact of anti-aging interventions, and predicting the emergence of age-related diseases. This review provides a detailed overview of the theoretical principles underlying the development of epigenetic clocks and their utility in aging research. Furthermore, it explores the existing obstacles and possibilities linked to epigenetic clocks and proposes potential avenues for future studies in this field., 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 Inc. All rights reserved.)

Plant responses to cold stress include either induction of flavonoid biosynthesis as part of defense responses or initially elevated levels of these substances to mitigate sudden temperature fluctuations. The role of chromatin modifying factors and, in general, epigenetic variability in these processes is not entirely clear. In this work, we review the literature to establish the relationship between flavonoids, cold and chromatin modifications. We demonstrate the relationship between cold acclimation and flavonoid accumulation, and then describe the cold adaptation signaling pathways and their relationship with chromatin modifying factors. Particular attention was paid to the cold signaling module OST1-HOS1-ICE1 and the novel function of the E3 ubiquitin protein ligase HOS1 (a protein involved in chromatin modification during cold stress) in flavonoid regulation., 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 Masson SAS. All rights reserved.)

Objectives: Second to fourth digit ratio is widely known indicator of prenatal sex hormones proportion. Higher prenatal androgenization results in longer fourth finger and lower 2D:4D index. The aim of this study was to determine whether the 2D:4D digit ratio is associated with DNA methylation (DNAm) age dependently on sex., Material and Methods: The study included 182 adults (106 females and 76 males) with a mean age of 51.5 ± 13 years. The investigation consisted of three main parts: a survey, anthropometric dimensions measurements (fingers length) and methylome analysis using collected blood samples. Genome-wide methylation was analyzed using EPIC microarray technology. Epigenetic age and epigenetic age acceleration were calculated using several widely applied algorithms., Results: Males with the female left hand pattern had more accelerated epigenetic age than those with the male pattern as calculated with PhenoAge and DNAmTL clocks., Conclusions: Finger female pattern 2D:4D above or equal to 1 in males is associated with epigenetic age acceleration, indicating that prenatal exposure to estrogens in males may be related to aging process in the later ontogenesis., (© 2024 Wiley Periodicals LLC.)

Despite the ongoing advances in interventional strategies (surgery, chemotherapy, radiotherapy, and immunotherapy) for managing pancreatic ductal adenocarcinoma (PDAC), the development of therapy refractory phenotypes remains a significant challenge. Resistance to various therapeutic modalities in PDAC emanates from a combination of inherent and acquired factors and is attributable to cancer cell-intrinsic and -extrinsic mechanisms. The critical determinants of therapy resistance include oncogenic signaling and epigenetic modifications that drive cancer cell stemness and metabolic adaptations, CAF-mediated stromagenesis that results in ECM deposition altered mechanotransduction, and secretome and immune evasion. We reviewed the current understanding of these multifaceted mechanisms operating in the PDAC microenvironment, influencing the response to chemotherapy, radiotherapy, and immunotherapy regimens. We then describe how the lessons learned from these studies can guide us to discover novel therapeutic regimens to prevent, delay, or revert resistance and achieve durable clinical responses., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: SKB is one of the co-founders of Sanguine Diagnostics and Therapeutics, Inc. The other authors declare no potential conflicts of interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Leukemia, although most likely starts as a monoclonal genetic/epigenetic anomaly, is a polyclonal disease at manifestation. This polyclonal nature results from ongoing evolutionary changes in the genome/epigenome of leukemia cells to promote their survival and proliferation advantages. We discuss here how genetic and/or epigenetic aberrations alter intracellular microenvironment in individual leukemia clones and how extracellular microenvironment selects the best fitted clones. This dynamic polyclonal composition of leukemia makes designing an effective therapy a challenging task especially because individual leukemia clones often display substantial differences in response to treatment. Here, we discuss novel therapeutic approach employing single cell multiomics to identify and eradicate all individual clones in a patient., (© 2024. The Author(s).)

Epigenetic alterations play a pivotal role in conditions influenced by environmental factors such as overweight and obesity. Many of these changes are tissue-specific, which entails a problem in its study since obtaining human tissue is a complex and invasive practice. While blood is widely used as a surrogate biomarker, it cannot directly extrapolate the evidence found in blood to tissue. Moreover, the intricacies of metabolic diseases add a new layer of complexity, as obesity leads to significant alterations in adipose tissue, potentially causing associated pathologies that can disrupt existing correlations seen in healthy individuals. Here, our objective was to determine which epigenetic markers exhibit correlations between blood and adipose tissue, regardless of the metabolic status. We collected paired blood and adipose tissue samples from 64 patients with morbidity obesity and non-obese and employed the MethylationEPIC 850 K array for analysis. We found that only a small fraction, specifically 4.3% (corresponding to 34,825 CpG sites), of the sites showed statistically significant correlations (R ≥ 0.6) between blood and adipose tissue. Within this subset, 5327 CpG sites exhibited a strong correlation (R ≥ 0.8) between blood and adipose tissue. Our findings suggest that the majority of epigenetic markers in peripheral blood do not reliably reflect changes occurring in visceral adipose tissues. However, it is important to note that there exists a distinct set of epigenetic markers that can indeed mirror changes in adipose tissue within blood samples. KEY MESSAGES: More than 8% of methylation sites exhibit similarity between blood and adipose tissues, regardless of BMI The correlation percentage between blood and adipose tissue is strongly influenced by gender The principal genes implicated in this correlation are related to metabolism or the immunological system., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Chronic rheumatological diseases are multifactorial conditions in which both the neuroendocrine hormone pathway, including cortisol, sex hormones and active vitamin D3 (calcitriol), all deriving from cholesterol, and the epigenetic modifications that they cause play an important role. In fact, epigenetics modulates the function of the DNA of immune cells, through three main mechanisms: DNA methylation, modifications to the histones that make up chromatin and production of non-coding RNAs (microRNA - miRNA). In this narrative review, the main data regarding the epigenetic modifications induced by cortisol, 17β-oestradiol, progesterone, testosterone and calcitriol on immune cells were collected, discussing how these can interfere in the predisposition and course of chronic rheumatological diseases (i.e. rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis). An ever-increasing number of miRNAs have been identified, which are produced by neuroendocrine hormones and can influence the inflammatory-fibrotic response at various levels. Concerning the involvements of the neuro-endocrine-immunology within the pathophysiology of rheumatic diseases, the epigenetic effects induced by steroid hormones must be taken into consideration to evaluate their impact on the progression of the single condition and even inside the single patient.

Background: DNA methylation levels at specific sites can be used to proxy C-reactive protein (CRP) levels, providing a potentially more stable and accurate indicator of sustained inflammation and associated health risk. However, its use has been primarily limited to adults or preterm infants, and little is known about determinants for - or offspring outcomes of - elevated levels of this epigenetic proxy in cord blood. The aim of this study was to comprehensively map prenatal predictors and long-term neurobehavioral outcomes of neonatal inflammation, as assessed with an epigenetic proxy of inflammation in cord blood, in the general pediatric population., Methods: Our study was embedded in the prospective population-based Generation R Study (n = 2,394). We created a methylation profile score of CRP (MPS-CRP) in cord blood as a marker of neonatal inflammation and validated it against serum CRP levels in mothers during pregnancy, as well as offspring at birth and in childhood. We then examined (i) which factors (previously associated with sustained inflammation) explain variability in MPS-CRP at birth, including a wide range of prenatal lifestyle and clinical conditions, pro-inflammatory exposures, as well as child genetic liability to elevated CRP levels; and (ii) whether MPS-CRP at birth associates with child neurobehavioral outcomes, including global structural MRI and DTI measures (child mean age 10 and 14 years) as well as psychiatric symptoms over time (Child Behavioral Checklist, at mean age 1.5, 3, 6, 10 and 14 years)., Results: MPS-CRP at birth was validated with serum CRP in cord blood (cut-off > 1 mg/L) (AUC = 0.72). Prenatal lifestyle pro-inflammatory factors explained a small part (i.e., < 5%) of the variance in the MPS-CRP at birth. No other prenatal predictor or the polygenic score of CRP in the child explained significant variance in the MPS-CRP at birth. The MPS-CRP at birth prospectively associated with a reduction in global fractional anisotropy over time on mainly a nominal threshold (β = -0.014, SE = 0.007, p = 0.032), as well as showing nominal associations with structural differences (amygdala [(β = 0.016, SE = 0.006, p = 0.010], cerebellum [(β = -0.007, SE = 0.003, p = 0.036]). However, no associations with child psychiatric symptoms were observed., Conclusion: Prenatal exposure to lifestyle-related pro-inflammatory factors was the only prenatal predictor that accounted for some of the individual variability in MPS-CRP levels at birth. Further, while the MPS-CRP prospectively associated with white matter alterations over time, no associations were observed at the behavioral level. Thus, the relevance and potential utility of using epigenetic data as a marker of neonatal inflammation in the general population remain unclear. In the future, the use of epigenetic proxies for a wider range of immune markers may lend further insights into the relationship between neonatal inflammation and adverse neurodevelopment within the general pediatric population., 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 The Author(s). Published by Elsevier Inc. All rights reserved.)

Dynamic alterations in cellular phenotypes during cancer progression are attributed to a phenomenon known as 'lineage plasticity'. This process is associated with therapeutic resistance and involves concurrent shifts in metabolic states that facilitate adaptation to various stressors inherent in malignant growth. Certain metabolites also serve as synthetic reservoirs for chromatin modification, thus linking metabolic states with epigenetic regulation. There remains a critical need to understand the mechanisms that converge on lineage plasticity and metabolic reprogramming to prevent the emergence of lethal disease. This review attempts to offer an overview of our current understanding of the interplay between metabolic reprogramming and lineage plasticity in the context of cancer, highlighting the intersecting drivers of cancer hallmarks, with an emphasis on solid tumors., Competing Interests: Declaration of interests The authors declare no conflicts of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Proneural gliomas are brain tumors characterized by enrichment of oligodendrocyte progenitor cell (OPC) transcripts and genetic alterations. In this study we sought to identify transcriptional and epigenetic differences between OPCs with Trp53 deletion and PDGF-BB overexpression (BB-p53n) and those carrying only p53 deletion (p53n). In culture, the BB-p53n OPCs display growth characteristics more similar to glioma cells than p53n OPCs. When injected in mouse brains, BB-p53n OPC form tumors, while the p53n OPCs do not. Unbiased histone proteomics and transcriptomic analysis on these OPC populations identified higher levels of the histone H3K27me3 mark and lower levels of the histone H4K20me3. The transcriptome of the BB-p53n OPCs was characterized by higher levels of transcripts related to proliferation and cell adhesion compared to p53n OPCs. Pharmacological inhibition of the enzyme responsible for histone H3K27 trimethylation (EZH2i) in BB-p53n OPCs, reduced cell cycle transcripts and increased the expression of differentiation markers, but was not sufficient to restore their growth characteristics. This suggests that PDGF-BB overexpression in p53n OPCs favors the early stages of transformation, by promoting proliferation and halting differentiation in a H3K27me3-dependent pathway, and favoring growth characteristics in a H3K27me3 independent manner., 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 Inc.)

Acute lymphoblastic leukemia (ALL) is the most common cancer in children. ALL originates from precursor lymphocytes that acquire multiple genomic changes over time, including chromosomal rearrangements and point mutations. While a large variety of genomic defects was identified and characterized in ALL over the past 30 years, it was only in recent years that the clonal heterogeneity was recognized. Thanks to the latest advancements in single-cell sequencing techniques, which have evolved from the analysis of a few hundred cells to the analysis of thousands of cells simultaneously, the study of tumor heterogeneity now becomes possible. Different modalities can be explored at the single-cell level: DNA, RNA, epigenetic modifications, and intracellular and cell surface proteins. In this review, we describe these techniques and highlight their advantages and limitations in the study of ALL biology. Moreover, multiomics technologies and the incorporation of the spatial dimension can provide insight into intercellular communication. We describe how the different single-cell sequencing technologies help to unravel the molecular complexity of ALL, shedding light on its development, its heterogeneity, its interaction with the leukemia microenvironment and possible relapse mechanisms., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Fruit development is essential for flowering plants' reproduction and a significant food source. Climate change threatens fruit yields due to its impact on pollination and fertilization processes, especially vulnerable to extreme temperatures, insufficient light, and pollinator decline. Parthenocarpy, the development of fruit without fertilization, offers a solution, ensuring yield stability in adverse conditions and enhancing fruit quality. Parthenocarpic fruits not only secure agricultural production but also exhibit improved texture, appearance, and shelf life, making them desirable for food processing and other applications. Recent research unveils the molecular mechanisms behind parthenocarpy, implicating transcription factors (TFs), noncoding RNAs, and phytohormones such as auxin, gibberellin (GA), and cytokinin (CK). Here we review recent findings, construct regulatory models, and identify areas for further research., Competing Interests: Declaration of interests No interests are declared., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

In order to address a biological explanation for the different regenerative abilities present among animals, a new evolutionary speculation is presented. It is hypothesized that epigenetic mechanisms have lowered or erased regeneration during the evolution of terrestrial invertebrates and vertebrates. The hypothesis indicates that a broad regeneration can only occur in marine or freshwater conditions, and that life on land does not allow for high regeneration. This is due to the physical, chemical and microbial conditions present in the terrestrial environment with respect to those of the aquatic environment. The present speculation provides examples of hypothetic evolutionary animal lineages that colonized the land, such as parasitic annelids, terrestrial mollusks, arthropods and amniotes. These are the animals where regeneration is limited or absent and their injuries are only repaired through limited healing or scarring. It is submitted that this loss derived from changes in the developmental gene pathways sustaining regeneration in the aquatic environment but that cannot be expressed on land. Once regeneration was erased in terrestrial species, re-adaptation to freshwater niches could not reactivate the previously altered gene pathways that determined regeneration. Therefore a broad regeneration was no longer possible or became limited and heteromorphic in the derived, extant animals. Only in few cases extensive healing abilities or regengrow, a healing process where regeneration overlaps with somatic growth, have evolved among arthropods and amniotes. The present paper is an extension of previous speculations trying to explain in biological terms the different regenerative abilities present among metazoans., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Schwannomas are benign tumors of the peripheral nervous system arising from the transformation of Schwann cells (SCs). On the whole, these tumors are related to alterations of the neurofibromin type 2 gene, coding for the oncosuppressor merlin, a cytoskeleton-associated protein belonging to the ezrin-radixin-moesin family. However, the underlying mechanisms of schwannoma onset and progression are not fully elucidated, whereas one of the challenges might be the environment. In this light, the exposure to electromagnetic field (EMF), generated by the use of common electrical devices, has been defiantly suggested as the cause of SCs transformation even if the evidence was mostly epidemiologic. Indeed, insubstantial mechanisms have been so far identified to explain SCs oncotransformation. Recently, some in vitro evidence pointed out alterations in proliferation and migration abilities in SCs exposed to EMF (0.1 T, 50 Hz, 10 min). Here, we used the same experimental paradigma to discuss the involvement of putative epigenetic mechanisms in SCs adaptation to EMF and to explain the occurrence of hypoxic alterations after the exposure. Our findings indicate a set of environmental-induced changes in SCs, toward a less-physiological state, which may be pathologically relevant for the SCs differentiation and the schwannoma development., (© 2024 The Author(s). Journal of Cellular Physiology published by Wiley Periodicals LLC.)

Upregulation of nuclear factor κB (NFκB) signaling is a hallmark of aging and a major cause of age-related chronic inflammation. However, its effect on cellular senescence remains unclear. Here, we show that alteration of NFκB nuclear dynamics from oscillatory to sustained by depleting a negative feedback regulator of NFκB pathway, NFκB inhibitor alpha (IκBα), in the presence of tumor necrosis factor α (TNFα) promotes cellular senescence. Sustained NFκB activity enhanced inflammatory gene expression through increased NFκB-DNA binding and slowed the cell cycle. IκBα protein was decreased under replicative or oxidative stress in vitro. Furthermore, a decrease in IκBα protein and an increase in DNA-NFκB binding at the transcription start sites of age-associated genes in aged mouse hearts suggested that nuclear NFκB dynamics may play a critical role in the progression of aging. Our study suggests that nuclear NFκB dynamics-dependent epigenetic changes regulated over time in a living system, possibly through a decrease in IκBα, enhance the expression of inflammatory genes to advance the cells to a senescent state., (© 2024 The Author(s). The FEBS Journal published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

Bipolar disorder (BD) is a complex and severe mental illness that causes significant suffering to patients. In addition to the burden of depressive and manic symptoms, patients with BD are at an increased risk for metabolic syndrome (MetS). MetS includes factors associated with an increased risk of atherosclerotic cardiovascular disease (CVD) and type 2 diabetes mellitus (T2DM), which may increase the mortality rate of patients with BD. Several studies have suggested a link between BD and MetS, which may be explained at an epigenetic level. We have focused on epigenetic mechanisms to review the causes of metabolic risk in BD., (© 2024 World Obesity Federation.)

Despite numerous studies demonstrate that genetics and epigenetics factors play important roles on smoking behavior, our understanding of their functional relevance and coordinated regulation remains largely unknown. Here we present a multiomics study on smoking behavior for Chinese smoker population with the goal of not only identifying smoking-associated functional variants but also deciphering the pathogenesis and mechanism underlying smoking behavior in this under-studied ethnic population. After whole-genome sequencing analysis of 1329 Chinese Han male samples in discovery phase and OpenArray analysis of 3744 samples in replication phase, we discovered that three novel variants located near FOXP1 (rs7635815), and between DGCR6 and PRODH (rs796774020), and in ARVCF (rs148582811) were significantly associated with smoking behavior. Subsequently cis-mQTL and cis-eQTL analysis indicated that these variants correlated significantly with the differential methylation regions (DMRs) or differential expressed genes (DEGs) located in the regions where these variants present. Finally, our in silico multiomics analysis revealed several hub genes, like DRD2, PTPRD, FOXP1, COMT, CTNNAP2, to be synergistic regulated each other in the etiology of smoking., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

We postulated that type 2 diabetes (T2D) predisposes patients to exocrine pancreatic diseases through (epi)genetic mechanisms. We explored the methylome (using MethylationEPIC arrays) of the exocrine pancreas in 141 donors, assessing the impact of T2D. An epigenome-wide association study of T2D identified hypermethylation in an enhancer of the pancreatic lipase-related protein 1 (PNLIPRP1) gene, associated with decreased PNLIPRP1 expression. PNLIPRP1 null variants (found in 191,000 participants in the UK Biobank) were associated with elevated glycemia and LDL cholesterol. Mendelian randomization using 2.5M SNP Omni arrays in 111 donors revealed that T2D was causal of PNLIPRP1 hypermethylation, which in turn was causal of LDL cholesterol. Additional AR42J rat exocrine cell analyses demonstrated that Pnliprp1 knockdown induced acinar-to-ductal metaplasia, a known prepancreatic cancer state, and increased cholesterol levels, reversible with statin. This (epi)genetic study suggests a role for PNLIPRP1 in human metabolism and exocrine pancreatic function, with potential implications for pancreatic diseases., (© 2024 by the American Diabetes Association.)

In this article, we review the main theories of biological aging, exploring the interaction of genetic, epigenetic, metabolic, immunological, and ecological factors in this process. For this purpose, we examine and discuss theories such as the allocation of metabolic resources, pleiotropic antagonism, genetic regulation, codon restriction, replicative senescence, action of free radicals, caloric restriction, catastrophic error, immunological theory, neuroendocrine theory, programmed aging, epigenetics of aging, grandmother and caregiver theories and ecological biophysical theory. We identify the contribution of different biological mechanisms to aging, emphasizing the complementarity of theories such as the allocation of metabolic resources, pleiotropic antagonism, and caloric restriction, providing a more comprehensive view of the phenomenon. In conclusion, we highlight the need to consider diverse perspectives in aging research, recognizing the absence of a single explanation. Integrating these theories is crucial to comprehensively understand the process and develop effective interventions in health and well-being in old age., (Copyright © 2024 SEGG. Publicado por Elsevier España, S.L.U. All rights reserved.)

Introduction: Epigenetic aging, a marker of biological aging measured by DNA methylation, may be affected by behaviors, including sleep and physical activity. However, investigations of physical activity and sleep with epigenetic aging among pediatric populations are scant and have not accounted for correlated behaviors., Methods: The study population included 472 Mexico City adolescents (52% female). Blood collection and 7-d wrist actigraphy (Actigraph GTX-BT) occurred during a follow-up visit when participants were 14.5 (2.09) yr. Leukocyte DNA methylation was measured with the Infinium MethylationEPIC array after bisulfite conversion, and nine epigenetic clocks were calculated. Sleep versus wake time was identified through a pruned dynamic programing algorithm, and physical activity was processed with Chandler cutoffs. Kmeans clustering was used to select actigraphy-assessed physical activity and sleep behavior clusters. Linear regression analyses were used to evaluate adjusted associations between the clusters and epigenetic aging., Results: There were three unique clusters: "Short sleep/high sedentary behavior," "Adequate sleep duration and late sleep timing/low moderate or vigorous physical activity (MVPA)," and "Adequate sleep duration/high MVPA." Compared with the "Adequate duration/high MVPA," adolescents with "Adequate duration and late sleep timing/low MVPA" had more accelerated aging for the GrimAge clock ( β = 0.63; 95% confidence interval, 0.07-1.19). In pubertal-stratified analyses, more mature adolescents in the "Adequate sleep duration and late sleep timing/low MVPA group" had accelerated epigenetic aging. In contrast, females in the "Short sleep/high sedentary" group had decelerated epigenetic aging for the Wu pediatric clock., Conclusions: Associations between behavior clusters and epigenetic aging varied by pubertal status and sex. Contrary results in the Wu clock suggest the need for future research on pediatric-specific clocks., (Copyright © 2024 by the American College of Sports Medicine.)

Phenotypic aging is ubiquitous across mammalian species, suggesting shared underlying mechanisms of aging. Aging is linked to molecular changes to DNA methylation and gene expression, and environmental factors, such as severe external challenges or adversities, can moderate these age-related changes. Yet, it remains unclear whether environmental adversities affect gene regulation via the same molecular pathways as chronological, or 'primary', aging. Investigating molecular aging in naturalistic animal populations can fill this gap by providing insight into shared molecular mechanisms of aging and the effects of a greater diversity of environmental adversities - particularly those that can be challenging to study in humans or laboratory organisms. Here, we characterised molecular aging - specifically, CpG methylation - in a sample of free-ranging rhesus macaques living off the coast of Puerto Rico (n samples = 571, n individuals = 499), which endured a major hurricane during our study. Age was associated with methylation at 78,661 sites (31% of all sites tested). Age-associated hypermethylation occurred more frequently in areas of active gene regulation, while hypomethylation was enriched in regions that show less activity in immune cells, suggesting these regions may become de-repressed in older individuals. Age-associated hypomethylation also co-occurred with increased chromatin accessibility while hypermethylation showed the opposite trend, hinting at a coordinated, multi-level loss of epigenetic stability during aging. We detected 32,048 CpG sites significantly associated with exposure to a hurricane, and these sites overlapped age-associated sites, most strongly in regulatory regions and most weakly in quiescent regions. Together, our results suggest that environmental adversity may contribute to aging-related molecular phenotypes in regions of active gene transcription, but that primary aging has specific signatures in non-regulatory regions., (© 2024 The Author(s). Molecular Ecology published by John Wiley & Sons Ltd.)

Maternal obesity (MO) is a significant cause of increased cardiometabolic risk in offspring, who present endothelial dysfunction at birth. Alterations in physiologic and cellular redox status are strongly associated with altered gene regulation in arterial endothelium. However, specific mechanisms by which the pro-oxidant fetal environment in MO could modulate the vascular gene expression and function during the offspring's postnatal life are elusive. We tested if oxidative stress could reprogram the antioxidant-coding gene's response to a pro-oxidant challenge through an epigenetic transcriptional memory (ETM) mechanism. A pro-oxidant double-hit protocol was applied to human umbilical artery endothelial cells (HUAECs) and EA.hy 926 endothelial cell lines. The ETM acquisition in the HMOX1 gene was analyzed by RT-qPCR. HMOX1 mRNA decay was evaluated by Actinomycin-D treatment and RT-qPCR. To assess the chromatin accessibility and the enrichment of NRF2, RNAP2, and phosphorylation at serin-5 of RNAP2, at HMOX1 gene regulatory regions, were used DNase HS-qPCR and ChIP-qPCR assays, respectively. The CpG methylation pattern at the HMOX1 core promoter was analyzed by DNA bisulfite conversion and Sanger sequencing. Data were analyzed using two-way ANOVA, and p < 0.05 was statistically significant. Using a pro-oxidant double-hit protocol, we found that the Heme Oxygenase gene (HMOX1) presents an ETM response associated with changes in the chromatin structure at the promoter and gene regulatory regions. The ETM response was characterized by a paused-RNA Polymerase 2 and NRF2 enrichment at the transcription start site and Enhancer 2 of the HMOX1 gene, respectively. Changes in DNA methylation pattern at the HMOX1 promoter were not a hallmark of this oxidative stress-induced ETM. These data suggest that a pro-oxidant milieu could trigger an ETM at the vascular level, indicating a potential epigenetic mechanism involved in the increased cardiovascular risk in the offspring of women with obesity., (© 2024 Wiley Periodicals LLC.)

Comprehensive N6-methyladenosine (m6A) epitranscriptomic profiling of primary tumors remains largely uncharted. Here, we profiled the m6A epitranscriptome of 10 nonneoplastic lung tissues and 51 lung adenocarcinoma (LUAD) tumors, integrating the corresponding transcriptomic, proteomic, and extensive clinical annotations. We identified distinct clusters and genes that were exclusively linked to disease progression through m6A modifications. In comparison with nonneoplastic lung tissues, we identified 430 transcripts to be hypo-methylated and 222 to be hyper-methylated in tumors. Among these genes, EML4 emerged as a novel metastatic driver, displaying significant hypermethylation in tumors. m6A modification promoted the translation of EML4, leading to its widespread overexpression in primary tumors. Functionally, EML4 modulated cytoskeleton dynamics by interacting with ARPC1A, enhancing lamellipodia formation, cellular motility, local invasion, and metastasis. Clinically, high EML4 protein abundance correlated with features of metastasis. METTL3 small-molecule inhibitor markedly diminished both EML4 m6A and protein abundance and efficiently suppressed lung metastases in vivo. Significance: Our study reveals a dynamic and functional epitranscriptomic landscape in LUAD, offering a valuable resource for further research in the field. We identified EML4 hypermethylation as a key driver of tumor metastasis, highlighting a novel therapeutic strategy of targeting EML4 to prevent LUAD metastasis., (©2024 The Authors; Published by the American Association for Cancer Research.)

Parkinson's disease (PD) is a prevalent and burdensome neurodegenerative disorder that has been extensively researched to understand its complex etiology, diagnosis, and treatment. The interplay between genetic and environmental factors in PD makes its pathophysiology difficult to comprehend, emphasizing the need for further investigation into genetic and epigenetic markers involved in the disease. Early diagnosis is crucial for optimal management of the disease, and the development of novel diagnostic biomarkers is ongoing. Although many efforts have been made in the field of recognition and interpretation of the mechanisms involved in the pathophysiology of the disease, the current knowledge about PD is just the tip of the iceberg. By scrutinizing genetic and epigenetic patterns underlying PD, new avenues can be opened for dissecting the pathology of the disorder, leading to more precise and efficient diagnostic and therapeutic approaches. This review emphasizes the importance of studying dysregulated cell signaling pathways and molecular processes associated with genes and epigenetic alterations in understanding PD, paving the way for the development of novel therapeutic strategies to combat this devastating disease., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Autism spectrum disorders (ASD) comprise a range of neurodevelopmental pathologies characterized by deficits in social interaction and repetitive behaviors, collectively affecting almost 1% of the worldwide population. Deciphering the etiology of ASD has proven challenging due to the intricate interplay of genetic and environmental factors and the variety of molecular pathways affected. Epigenomic alterations have emerged as key players in ASD etiology. Their research has led to the identification of biomarkers for diagnosis and pinpointed specific gene targets for therapeutic interventions. This review examines the role of epigenetic alterations, resulting from both genetic and environmental influences, as a central causative factor in ASD, delving into its contribution to pathogenesis and treatment strategies., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Sirtuin 7 (SIRT7) is a member of the sirtuin family and has emerged as a key player in numerous cellular processes. It exhibits various enzymatic activities and is predominantly localized in the nucleolus, playing a role in ribosomal RNA expression, DNA damage repair, stress response and chromatin compaction. Recent studies have revealed its involvement in diseases such as cancer, cardiovascular and bone diseases, and obesity. In cancer, SIRT7 has been found to be overexpressed in multiple types of cancer, including breast cancer, clear cell renal cell carcinoma, lung adenocarcinoma, prostate adenocarcinoma, hepatocellular carcinoma, and gastric cancer, among others. In general, cancer cells exploit SIRT7 to enhance cell growth and metabolism through ribosome biogenesis, adapt to stress conditions and exert epigenetic control over cancer-related genes. The aim of this review is to provide an in-depth understanding of the role of SIRT7 in cancer carcinogenesis, evolution and progression by elucidating the underlying molecular mechanisms. Emphasis is placed on unveiling the intricate molecular pathways through which SIRT7 exerts its effects on cancer cells. In addition, this review discusses the feasibility and challenges associated with the development of drugs that can modulate SIRT7 activity., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Cold stress in low-temperature environments can trigger changes in gene expression, but epigenomics regulation of temperature stability in vital tissues, including the fat and diencephalon, is still unclear. Here, we explore the cold-induced changes in epigenomic features in the diencephalon and fat tissues of two cold-resistant Chinese pig breeds, Min and Enshi black (ES) pigs, utilizing H3K27ac CUT&Tag, RNA-seq, and selective signature analysis. Our results show significant alterations in H3K27ac modifications in the diencephalon of Min pigs and the fat of ES pigs after cold exposure. Dramatic changes in H3K27ac modifications in the diencephalon of Min pig are primarily associated with genes involved in energy metabolism and hormone regulation, whereas those in the fat of ES pig are primarily associated with immunity-related genes. Moreover, transcription factors PRDM1 and HSF1, which show evidence of selection, are enriched in genomic regions presenting cold-responsive alterations in H3K27ac modification in the Min pig diencephalon and ES pig fat, respectively. Our results indicate the diversity of epigenomic response mechanisms to cold exposure between Min and ES pigs, providing unique epigenetic resources for studies of low-temperature adaptation in large mammals., Competing Interests: Conflict of interest The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background & Aims: Chronic HCV infection results in abnormal immunological alterations, which are not fully normalized after viral elimination by direct-acting antiviral (DAA) treatment. Herein, we longitudinally examined phenotypic, transcriptomic, and epigenetic alterations in peripheral blood regulatory T (Treg) cells from patients with chronic HCV infection before, during, and after DAA treatment., Methods: Patients with chronic genotype 1b HCV infection who achieved sustained virologic response by DAA treatment and age-matched healthy donors were recruited. Phenotypic characteristics of Treg cells were investigated through flow cytometry analysis. Moreover, the transcriptomic and epigenetic landscapes of Treg cells were analyzed using RNA sequencing and ATAC-seq (assay for transposase-accessible chromatin with sequencing) analysis., Results: The Treg cell population - especially the activated Treg cell subpopulation - was expanded in peripheral blood during chronic HCV infection, and this expansion was sustained even after viral clearance. RNA sequencing analysis revealed that viral clearance did not abrogate the inflammatory features of these Treg cells, such as Treg activation and TNF signaling. Moreover, ATAC-seq analysis showed inflammatory imprinting in the epigenetic landscape of Treg cells from patients, which remained after treatment. These findings were further confirmed by intracellular cytokine staining, demonstrating that Treg cells exhibited inflammatory features and TNF production in chronic HCV infection that were maintained after viral clearance., Conclusions: Overall, our results showed that during chronic HCV infection, the expanded Treg cell population acquired inflammatory features at phenotypic, transcriptomic, and epigenetic levels, which were maintained even after successful viral elimination by DAA treatment. Further studies are warranted to examine the clinical significance of sustained inflammatory features in the Treg cell population after recovery from chronic HCV infection., Impact and Implications: During chronic HCV infection, several immune components are altered both quantitatively and qualitatively. The recent introduction of direct-acting antivirals has led to high cure rates. Nevertheless, we have demonstrated that inflammatory features of Treg cells are maintained at phenotypic, transcriptomic, and epigenetic levels even after successful DAA treatment. Further in-depth studies are required to investigate the long-term clinical outcomes of patients who have recovered from chronic HCV infection., (Copyright © 2024 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

In view of the increasing risk of neurodegenerative diseases, epigenetics plays a fundamental role in the field of neuroscience. Several modifications have been studied including DNA methylation, histone acetylation, histone phosphorylation, etc. Histone acetylation and deacetylation regulate gene expression, and the regular activity of histone acetyltransferases (HATs) and histone deacetylases (HDACs) provides regulatory stages for gene expression and cell cycle. Imbalanced homeostasis in these enzymes causes a detrimental effect on neurophysiological function. Intriguingly, epigenetic remodelling via histone acetylation in certain brain areas has been found to play a key role in the neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and Huntington's disease. It has been demonstrated that a number of HATs have a role in crucial brain processes such regulating neuronal plasticity and memory formation. The most recent therapeutic methods involve the use of small molecules known as histone deacetylase (HDAC) inhibitors that antagonize HDAC activity thereby increase acetylation levels in order to prevent the loss of HAT function in neurodegenerative disorders. The target specificity of the HDAC inhibitors now in use raises concerns about their applicability, despite the fact that this strategy has demonstrated promising therapeutic outcomes. The aim of this review is to summarize the cross-linking between histone modification and its regulation in the pathogenesis of neurological disorders. Furthermore, these findings also support the notion of new pharmacotherapies that target particular areas of the brain using histone deacetylase inhibitors., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Cancer drug resistance poses a significant obstacle to successful chemotherapy, primarily driven by the activity of ATP-binding cassette (ABC) transporters, which actively efflux chemotherapeutic agents from cancer cells, reducing their intracellular concentrations and therapeutic efficacy. Recent studies have highlighted the pivotal role of long noncoding RNAs (lncRNAs) in regulating this resistance, positioning them as crucial modulators of ABC transporter function. lncRNAs, once considered transcriptional noise, are now recognized for their complex regulatory capabilities at various cellular levels, including chromatin modification, transcription, and post-transcriptional processing. This review synthesizes current research demonstrating how lncRNAs influence cancer drug resistance by modulating the expression and activity of ABC transporters. lncRNAs can act as molecular sponges, sequestering microRNAs that would otherwise downregulate ABC transporter genes. Additionally, they can alter the epigenetic landscape of these genes, affecting their transcriptional activity. Mechanistic insights reveal that lncRNAs contribute to the activity of ABC transporters, thereby altering the efflux of chemotherapeutic drugs and promoting drug resistance. Understanding these interactions provides a new perspective on the molecular basis of chemoresistance, emphasizing the regulatory network of lncRNAs and ABC transporters. This knowledge not only deepens our understanding of the biological mechanisms underlying drug resistance but also suggests novel therapeutic strategies. In conclusion, the intricate interplay between lncRNAs and ABC transporters is crucial for developing innovative solutions to combat cancer drug resistance, underscoring the importance of continued research in this field., (© 2024 International Union of Biochemistry and Molecular Biology.)

Pan-vascular diseases, based on systems biology theory, explore the commonalities and individualities of important target organs such as cardiovascular, cerebrovascular and peripheral blood vessels, starting from the systemic and holistic aspects of vascular diseases. The purpose is to understand the interrelationships and results between them, achieve vascular health or sub-health, and comprehensively improve the physical and mental health of the entire population. Post-translational modification (PTM) is an important part of epigenetics, including phosphorylation, acetylation, ubiquitination, methylation, etc., playing a crucial role in the pan-vascular system. Crotonylation is a novel type of PTM that has made significant progress in the research of pan-vascular related diseases in recent years. Based on the review of previous studies, this article summarises the various regulatory factors of crotonylation, physiological functions and the mechanisms of histone and non-histone crotonylation in regulating pan-vascular related diseases to explore the possibility of precise regulation of crotonylation sites as potential targets for disease treatment and the value of clinical translation.

Cardiac fibrosis is a significant driver of congestive heart failure, a syndrome that continues to affect a growing patient population globally. Cardiac fibrosis results from a constellation of complex processes at the transcription, receptor, and signaling axes levels. Various mediators and signaling cascades, such as the transformation growth factor-beta pathway, have been implicated in the pathophysiology of cardiac tissue fibrosis. Our understanding of these markers and pathways has improved in recent years as more advanced technologies and assays have been developed, allowing for better delineation of the crosstalk between specific factors. There is mounting evidence suggesting that epigenetic modulation plays a pivotal role in the progression of cardiac fibrosis. Transcriptional regulation of key pro- and antifibrotic pathways can accentuate or blunt the rate and extent of fibrosis at the tissue level. Exosomes, micro-RNAs, and long noncoding RNAs all belong to factors that can impact the epigenetic signature in cardiac fibrosis. Herein, we comprehensively review the latest literature about exosomes, their contents, and cardiac fibrosis. In doing so, we highlight the specific transcriptional factors with pro- or antifibrotic properties. We also assimilate the data supporting these mediators' potential utility as diagnostic or prognostic biomarkers. Finally, we offer insight into where further work can be done to fill existing gaps to translate preclinical findings better and improve clinical outcomes., 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 The Author(s). Published by Elsevier Inc. All rights reserved.)

In this review we discuss how the mammalian interfollicular epidermis forms during development, maintains homeostasis, and is repaired following wounding. Recent studies have provided new insights into the relationship between the stem cell compartment and the differentiating cell layers; the ability of differentiated cells to dedifferentiate into stem cells; and the epigenetic memory of epidermal cells following wounding., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

DNA methylation has been proposed to be an important mechanism that allows plants to respond to their environments sometimes entirely uncoupled from genetic variation. To understand the genetic basis, biological functions and climatic relationships of DNA methylation at a population scale in Arabidopsis thaliana, we performed a genome-wide association analysis with high-quality single nucleotide polymorphisms (SNPs), and found that ~56% on average, especially in the CHH sequence context (71%), of the differentially methylated regions (DMRs) are not tagged by SNPs. Among them, a total of 3235 DMRs are significantly associated with gene expressions and potentially heritable. 655 of the 3235 DMRs are associated with climatic variables, and we experimentally verified one of them, HEI10 (HUMAN ENHANCER OF CELL INVASION NO.10). Such epigenetic loci could be subjected to natural selection thereby affecting plant adaptation, and would be expected to be an indicator of accessions at risk. We therefore incorporated these climate-related DMRs into a gradient forest model, and found that the natural A. thaliana accessions in Southern Europe that may be most at risk under future climate change. Our findings highlight the importance of integrating DNA methylation that is independent of genetic variations, and climatic data to predict plants' vulnerability to future climate change., (© 2024 John Wiley & Sons Ltd.)

Plants can program and reprogram their genomes to create genetic variation and epigenetic modifications, leading to phenotypic plasticity. Although consequences of genetic changes are comprehensible, the basis for transgenerational inheritance of epigenetic variation is elusive. This review addresses contributions of external (environmental) and internal (genomic) factors to the establishment and maintenance of epigenetic memory during plant evolution, crop domestication, and modern breeding. Dynamic and pervasive changes in DNA methylation and chromatin modifications provide a diverse repertoire of epigenetic variation potentially for transgenerational inheritance. Elucidating and harnessing epigenetic inheritance will help us develop innovative breeding strategies and biotechnological tools to improve crop yield and resilience in the face of environmental challenges. Beyond plants, epigenetic principles are shared across sexually reproducing organisms including humans with relevance to medicine and public health., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Most childhood cancers possess distinct clinicopathological profiles from those seen in adulthood, reflecting their divergent mechanisms of carcinogenesis. Rather than depending on the decades-long, stepwise accumulation of changes within a mature cell that defines adult carcinomas, many pediatric malignancies emerge rapidly as the consequence of random errors during development. These errors-whether they be genetic, epigenetic, or microenvironmental-characteristically block maturation, resulting in phenotypically primitive neoplasms. Only an event that falls within a narrow set of spatiotemporal parameters will forge a malignant clone; if it occurs too soon then the event might be lethal, or negatively selected against, while if it is too late or in an incorrectly primed precursor cell then the necessary intracellular conditions for transformation will not be met. The precise characterization of these changes, through the study of normal tissues and tumors from patients and model systems, will be essential if we are to develop new strategies to diagnose, treat, and perhaps even prevent childhood cancer., (Copyright © 2024 Cold Spring Harbor Laboratory Press; all rights reserved.)

Spatial epigenetic mapping of tissues enables the study of gene regulation programs and cellular functions with the dependency on their local tissue environment. Here we outline a complete procedure for two spatial epigenomic profiling methods: spatially resolved genome-wide profiling of histone modifications using in situ cleavage under targets and tagmentation (CUT&Tag) chemistry (spatial-CUT&Tag) and transposase-accessible chromatin sequencing (spatial-ATAC-sequencing) for chromatin accessibility. Both assays utilize in-tissue Tn5 transposition to recognize genomic DNA loci followed by microfluidic deterministic barcoding to incorporate spatial address codes. Furthermore, these two methods do not necessitate prior knowledge of the transcription or epigenetic markers for a given tissue or cell type but permit genome-wide unbiased profiling pixel-by-pixel at the 10 μm pixel size level and single-base resolution. To support the widespread adaptation of these methods, details are provided in five general steps: (1) sample preparation; (2) Tn5 transposition in spatial-ATAC-sequencing or antibody-controlled pA-Tn5 tagmentation in CUT&Tag; (3) library preparation; (4) next-generation sequencing; and (5) data analysis using our customed pipelines available at: https://github.com/dyxmvp/Spatial&#95;ATAC-seq and https://github.com/dyxmvp/spatial-CUT-Tag . The whole procedure can be completed on four samples in 2-3 days. Familiarity with basic molecular biology and bioinformatics skills with access to a high-performance computing environment are required. A rudimentary understanding of pathology and specimen sectioning, as well as deterministic barcoding in tissue-specific skills (e.g., design of a multiparameter barcode panel and creation of microfluidic devices), are also advantageous. In this protocol, we mainly focus on spatial profiling of tissue region-specific epigenetic landscapes in mouse embryos and mouse brains using spatial-ATAC-sequencing and spatial-CUT&Tag, but these methods can be used for other species with no need for species-specific probe design., (© 2024. Springer Nature Limited.)

Background: Higher diet quality scores are associated with a lower risk for many chronic diseases and all-cause mortality; however, it is unclear if diet quality is associated with aging biology., Objective: This study aimed to examine the association between diet quality and a measure of biological aging known as epigenetic aging., Design: A cross-sectional data analysis was used to examine the association between three diet quality scores based on self-reported food frequency questionnaire data and five measures of epigenetic aging based on DNA methylation (DNAm) data from peripheral blood., Participants/setting: This study included 4,500 postmenopausal women recruited from multiple sites across the United States (1993-98), aged 50 to 79 years, with food frequency questionnaire and DNAm data available from the Women's Health Initiative baseline visit., Main Outcome Measures: Five established epigenetic aging measures were generated from HumanMethylation450 Beadchip DNAm data, including AgeAccelHannum, AgeAccelHorvath, AgeAccelPheno, AgeAccelGrim, and DunedinPACE., Statistical Analyses Performed: Linear mixed models were used to test for associations between three diet quality scores (Healthy Eating Index, Dietary Approaches to Stop Hypertension, and alternate Mediterranean diet scores) and epigenetic aging measures, adjusted for age, race and ethnicity, education, tobacco smoking, physical activity, Women's Health Initiative substudy from which DNAm data were obtained, and DNAm-based estimates of leukocyte proportions., Results: Healthy Eating Index, Dietary Approaches to Stop Hypertension, and alternate Mediterranean diet scores were all inversely associated with AgeAccelPheno, AgeAccelGrim, and DunedinPACE (P < 0.05), with the largest effects with DunedinPACE. A one standard deviation increment in diet quality scores was associated with a decrement (β ± SE) in DunedinPACE z score of -0.097 ± 0.014 (P = 9.70 x 10 -13 ) for Healthy Eating Index, -0.107 ± 0.014 (P = 1.53 x 10 -14 ) for Dietary Approaches to Stop Hypertension, and -0.068 ± 0.013 (P = 2.31 x 10 -07 ) for the alternate Mediterranean diet., Conclusions: In postmenopausal women, diet quality scores were inversely associated with DNAm-based measures of biological aging, particularly DunedinPACE., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

The ectoderm is the outermost of the three germ layers of the early embryo that arise during gastrulation. Once the germ layers are established, the complex interplay of cellular proliferation, differentiation, and migration results in organogenesis. The ectoderm is the progenitor of both the surface ectoderm and the neural ectoderm. Notably, the surface ectoderm develops into the epidermis and its associated appendages, nails, external exocrine glands, olfactory epithelium, and the anterior pituitary. Specification, development, and homeostasis of these organs demand a tightly orchestrated gene expression program that is often dictated by epigenetic regulation. In this review, we discuss the recent discoveries that have highlighted the importance of chromatin regulatory mechanisms mediated by transcription factors, histone and DNA modifications that aid in the development of surface ectodermal organs and maintain their homeostasis post-development., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The processes of epidermal development in mammals are regulated by complex molecular mechanisms, such as histone modifications. Histone H3 lysine K4 methylation mediated by COMPASS (complex of proteins associated with Set1) methyltransferase is associated with gene activation, but its effect on epidermal lineage development remains unclear. Therefore, we constructed a mouse model of specific ASH2L (COMPASS methyltransferase core subunit) deletion in epidermal progenitor cells and investigated its effect on the development of mouse epidermal lineage. Furthermore, downstream target genes regulated by H3K4me3 were screened using RNA sequencing combined with Cleavage Under Targets and Tagmentation sequencing. Deletion of ASH2L in epidermal progenitor cells caused thinning of the suprabasal layer of the epidermis and delayed hair follicle morphogenesis in newborn mice. These phenotypes may be related to the reduced proliferative capacity of epidermal and hair follicle progenitor cells. ASH2L depletion may also lead to depletion of the epidermal stem cell pools in late mouse development. Finally, genes related to hair follicle development (Shh, Edar, and Fzd6), Notch signaling pathway (Notch2, Notch3, Hes5, and Nrarp), and ΔNp63 were identified as downstream target genes regulated by H3K4me3. Collectively, ASH2L-dependent H3K4me3 modification served as an upstream epigenetic regulator in epidermal differentiation and hair follicle morphogenesis in mice., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Epigenetic aging clocks have been widely used to validate rejuvenation effects during cellular reprogramming. However, these predictions are unverifiable because the true biological age of reprogrammed cells remains unknown. We present an analytical framework to consider rejuvenation predictions from the uncertainty perspective. Our analysis reveals that the DNA methylation profiles across reprogramming are poorly represented in the aging data used to train clock models, thus introducing high epistemic uncertainty in age estimations. Moreover, predictions of different published clocks are inconsistent, with some even suggesting zero or negative rejuvenation. While not questioning the possibility of age reversal, we show that the high clock uncertainty challenges the reliability of rejuvenation effects observed during in vitro reprogramming before pluripotency and throughout embryogenesis. Conversely, our method reveals a significant age increase after in vivo reprogramming. We recommend including uncertainty estimation in future aging clock models to avoid the risk of misinterpreting the results of biological age prediction., (© 2024 The Author(s). Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.)