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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. [ABSTRACT FROM AUTHOR]

Diabetes mellitus and its complications exploit significantly impact global human well-being and economic burden. Previous studies and clinical trials have provided insights into the concept of metabolic memory, which sustains even after hyperglycemia has been resolved, causing diabetic complications completely. The term "metabolic memory" refers to the body's abnormal metabolism, which can have long-term effects and influence both health and disease conditions. It involves various molecular processes causing cellular shifts, tissue and organ dysfunctions, disease progression, and effects on offspring. The conceptual framework of metabolic memory is defined and strengthened, offering a comprehensive understanding of the underlying causes of diabetic nephropathy (DN) and providing a potential new approach for diagnosing and treating the disease. In this review, we elucidated the importance, characteristics, cellular and molecular importance, and therapeutic intervention to eradicate metabolic memory in DN once hyperglycemia has been eliminated. The regulation of metabolic memory is assisted based on an epigenetic mechanism. Therefore, this report traces the significant factors involved in regulating epigenetic modifications such as DNA methylation, histone modification, and chromatin remodeling. This mechanism significantly triggers epigenetic regulation, leading to glucose stress, oxidative stress induction, and apoptosis, causing DN. It occurs beyond various signaling cascades, resulting in alterations in transcription factors and receptor molecules, which enhance the metabolic memory in the post-sustenance of hyperglycemia. This condition can be modulated based on therapeutic interventions involving lifestyle modification and the inclusion of natural substances like bioactive compounds, polyphenols, and terpenoids in the diet, followed by medications acting as epigenetic modifiers. [ABSTRACT FROM AUTHOR]

Persistent inflammation is a major contributor in the development of various inflammatory diseases like atherosclerosis. Our study investigates how transient receptor potential vanilloid 4 (TRPV4), a mechanosensitive ion channel, interacts with microRNA-146a (miR-146a), within the context of inflammation and atherosclerosis. Micro-RNAs play a critical role in controlling gene expression, and miR-146a is notable for its anti-inflammatory actions. TRPV4 is activated by diverse soluble and mechanical stimuli, and often associated with inflammatory responses in various diseases. Here, we find that TRPV4 negatively regulates miR-146a expression in macrophages, especially following stimulation by lipopolysaccharides or alterations in matrix stiffness. We show that in atherosclerosis, a condition characterized by matrix stiffening, TRPV4 decreases miR-146a expression in aortic tissue macrophages. We find that TRPV4's impacton miR-146a is independent of activation of NFkB, Stat1, P38, and AKT, but is rather mediated through a mechanism involving histone deacetylation instead of DNA methylation at the miR-146a promoter site. Furthermore, we show that N-terminal residues 1 to 130 in TRPV4 is essential in suppression of miR-146a expression in LPS-stimulated macrophages. Altogether, this study identifies a regulatory mechanism of miR-146a expression by TRPV4 which may open new potential therapeutic strategies for managing inflammatory diseases. [ABSTRACT FROM AUTHOR]

Methylation, a key epigenetic modification, is essential for regulating gene expression and protein function without altering the DNA sequence, contributing to various biological processes, including gene transcription, embryonic development, and cellular functions. Methylation encompasses DNA methylation, RNA methylation and histone modification. Recent research indicates that DNA methylation is vital for establishing and maintaining normal brain functions by modulating the high-order structure of DNA. Alterations in the patterns of DNA methylation can exert significant impacts on both gene expression and cellular function, playing a role in the development of numerous diseases, such as neurological disorders, cardiovascular diseases as well as cancer. Our current understanding of the etiology of neurological diseases emphasizes a multifaceted process that includes neurodegenerative, neuroinflammatory, and neurovascular events. Epigenetic modifications, especially DNA methylation, are fundamental in the control of gene expression and are critical in the onset and progression of neurological disorders. Furthermore, we comprehensively overview the role and mechanism of DNA methylation in in various biological processes and gene regulation in neurological diseases. Understanding the mechanisms and dynamics of DNA methylation in neural development can provide valuable insights into human biology and potentially lead to novel therapies for various neurological diseases. [ABSTRACT FROM AUTHOR]

Myocardial fibroblasts play a crucial role in heart structure and function. In recent years, significant progress has been made in understanding the epigenetic regulation of myocardial fibroblasts, which is essential for cardiac development, homeostasis, and disease progression. In healthy hearts, cardiac fibroblasts (CFs) play a crucial role in synthesizing the extracellular matrix (ECM) when in a dormant state. However, under pathological and environmental stress, CFs transform into activated fibroblasts known as myofibroblasts. These myofibroblasts produce an excess of ECM, which promotes cardiac fibrosis. Although multiple molecular mechanisms are associated with CF activation and myocardial dysfunction, emerging evidence highlights the significant involvement of epigenetic regulation in this process. Epigenetics refers to the heritable changes in gene expression that occur without altering the DNA sequence. These mechanisms have emerged as key regulators of myocardial fibroblast function. This review focuses on recent advancements in the understanding of the role of epigenetic regulation and emphasizes the impact of epigenetic modifications on CF activation. Furthermore, we present perspectives and prospects for future research on epigenetic modifications and their implications for myocardial fibroblasts. [ABSTRACT FROM AUTHOR]

Human rhinovirus (HRV) infections are the leading cause of disease exacerbations in individuals with chronic pulmonary diseases, primarily due to impaired macrophage functions, resulting in defective bacterial elimination. We previously demonstrated that HRV16 impairs macrophages' functions in an ARL5b-dependent manner. In permissive cells, ARL5b acted as an HRV16 restriction factor and was repressed. Here, we delve into the dual regulation of ARL5b by HRV16 in both cell types. We analyzed the effect of HRV16 on primary human macrophages using neutralizing antibodies, specific inhibitors, siRNA, and chromatin immune precipitation. Our study reveals that, while the virus does not replicate in macrophages, it induces interferon and pro-inflammatory responses. We identify the ICAM-1-PKR-ATF2 signaling axis as crucial for ARL5b induction in macrophages, whereas only ICAM-1 plays a role in ARL5b repression in permissive cells. Furthermore, HRV16 triggers epigenetic reprogramming in both cell types at the ARL5b promoter. In macrophages, epigenetic changes are ATF2 dependent. In conclusion, our findings highlight previously unknown signaling pathways activated by HRV16 in macrophages. Targeting these pathways could offer novel strategies to improve outcomes for individuals with respiratory conditions. [ABSTRACT FROM AUTHOR]

The interplay between mitochondria, epigenetics, and the microbiota is intricately linked to both health and disease. Within our cells, a complex molecular dance occurs, where these components intertwine in a mesmerizing ballet that plays a decisive role in our health. Mitochondria, beyond being energy powerhouses, modulate nuclear gene expression through messengers like reactive oxidative stress (ROS) and calcium. Epigenetics, acting as the molecular conductor, regulates the expression of both nuclear and mitochondrial genes through modifications like DNA methylation. The intestinal microbiota itself produces short-chain fatty acids (SCFAs) that influence mitochondrial activity. SCFA-induced epigenetic modifications, like histone acetylation, impact mitochondrial function which may lead to disease. Mitochondrial dysfunction generates retrograde signals that alter nuclear gene expression, as evidenced by increased histone H3 lysine 27 acetylation (H3K27ac) in genes essential for neuronal differentiation and mitochondrial reprogramming. Alterations in the mitochondrial-nuclear-microbiota axis are associated with diseases including diabetes, neurodegeneration, and cancer. Modulating the intestinal microbiota with probiotics or prebiotics can restore balance while intervening in mitochondrial pathways, which can be a therapeutic strategy. Additionally, using epigenetic agents like histone deacetylase (HDAC) inhibitors can reprogram gene expression and improve mitochondrial function. Finally, the present review aims to explore the central interplay between mitochondria, epigenetics modifications, and microbiota in a complex and dynamic molecular context that plays a fundamental role in human health. Specifically, it will examine the impact of microbiome components and metabolites generated from normobiosis and dysbiosis on mitochondria and epigenetic modifications across different diseases and metabolic conditions. This integrated understanding of the molecular players and their interactions provides a deeper perspective on how to promote health and potentially combat disease. [ABSTRACT FROM AUTHOR]

As a treasure trove of natural products (NPs), various fungal species possess great potential as cell factories for valuable NPs bioproduction. However, they have many silent biosynthetic gene clusters (BGCs), and activation of BGCs expression is critical to the discovery of their indetectable NPs, especially secondary metabolites, in which epigenetic regulation plays a significant role. Thanks to the development of sequencing technologies, more and more epigenetic regulators have been characterized and adopted for boosting fungal NPs production. In this review, at first we summarize various kinds of epigenetic regulation and relevant strategies for triggering fungal NPs biosynthesis. Then, we discuss the limitations of the current strategies, and propose future trends in the discovery of fungi derived NPs by manipulating epigenetics. • Epigenetic regulation plays a significant role in discovery of the undetectable natural products from fungal species. • Manipulating histone-modifying proteins is a novel manner to activate the expression of biosynthetic gene clusters. • This work provides a systematical view on triggering fungal natural products biosynthesis by epigenetic regulation. [ABSTRACT FROM AUTHOR]

Climate change has emerged as a crucial global issue that significantly threatens the survival of plants. In particular, low temperature (LT) is one of the critical environmental factors that influence plant morphological, physiological, and biochemical changes during both the vegetative and reproductive growth stages. LT, including abrupt drops in temperature, as well as winter conditions, can cause detrimental effects on the growth and development of tomato plants, ranging from sowing, transplanting, truss appearance, flowering, fertilization, flowering, fruit ripening, and yields. Therefore, it is imperative to understand the comprehensive mechanisms underlying the adaptation and acclimation of tomato plants to LT, from the morphological changes to the molecular levels. In this review, we discuss the previous and current knowledge of morphological, physiological, and biochemical changes, which contain vegetative and reproductive parameters involving the leaf length (LL), plant height (PH) stem diameter (SD), fruit set (FS), fruit ripening (FS), and fruit yield (FY), as well as photosynthetic parameters, cell membrane stability, osmolytes, and ROS homeostasis via antioxidants scavenging systems during LT stress in tomato plants. Moreover, we highlight recent advances in the understanding of molecular mechanisms, including LT perception, signaling transduction, gene regulation, and fruit ripening and epigenetic regulation. The comprehensive understanding of LT response provides a solid basis to develop the LT-resistant varieties for sustainable tomato production under the ever-changing temperature fluctuations. [ABSTRACT FROM AUTHOR]

Anthropogenic activities and subsequent global climate change instigate drastic crop productivity and yield changes. These changes comprise a rise in the number and severity of plant stress factors, which can arise simultaneously or sequentially. When abiotic stress factors are combined, their impact on plants is more substantial than that of a singleton stress factor. One such impact is the alteration of redox cellular homeostasis, which, in turn, can regulate downstream stress-responsive gene expression and resistance response. The epigenetic regulation of gene expression in response to varied stress factors is an interesting phenomenon, which, conversely, can be stable and heritable. The epigenetic control in plants in response to abiotic stress combinations and their interactions with cellular redox alteration is an emerging field to commemorate crop yield management under climate change. The article highlights the integration of the redox signaling pathways and epigenetic regulations as pivotal components in the complex network of plant responses against multicombinatorial stresses across time and space. This review aims to lay the foundation for developing novel approaches to mitigate the impact of environmental stresses on crop productivity, bridging the gap between theoretical understanding and practical solutions in the face of a changing climate and anthropogenic disturbances. [ABSTRACT FROM AUTHOR]

Laryngeal squamous cell carcinoma (LSCC) is the most prevalent form of laryngeal cancer. Currently, a combination of surgery and chemoradiotherapy has shown promising outcomes. However, the survival rate in late stages remains low and the pathogenesis is not fully understood. In recent years, there has been an increasing focus on identifying new biomarkers for predicting and treating LSCC. It has been established that long non-coding RNAs (IncRNAs) plays a significant role as regulatory factors in the onset and progression of LSCC. This article aims to explore the regulatory function and mechanism of lncRNA in the development of LSCC, offering insights for molecular biological therapy targeting LSCC. [ABSTRACT FROM AUTHOR]

Epigenetic regulation plays a central role in the regulation of a number of cellular processes such as proliferation, differentiation, cell cycle, and apoptosis. In particular, small molecule epigenetic modulators are key elements that can effectively influence gene expression by precisely regulating the epigenetic state of cells. To identify useful small-molecule regulators that enhance the expression of recombinant proteins in Chinese hamster ovary (CHO) cells, we examined a novel dual-HDAC/LSD1 inhibitor I-4 as a supplement for recombinant CHO cells. Treatment with 2 μM I-4 was most effective in increasing monoclonal antibody production. Despite cell cycle arrest at the G1/G0 phase, which inhibits cell growth, the addition of the inhibitor at 2 µM to monoclonal antibody-expressing CHO cell cultures resulted in a 1.94-fold increase in the maximal monoclonal antibody titer and a 2.43-fold increase in specific monoclonal antibody production. In addition, I-4 significantly increased the messenger RNA levels of the monoclonal antibody and histone H3 acetylation and methylation levels. We also investigated the effect on HDAC-related isoforms and found that interference with the HDAC5 gene increased the monoclonal antibody titer by 1.64-fold. The results of this work provide an effective method of using epigenetic regulatory strategies to enhance the expression of recombinant proteins in CHO cells. Key points: • HDAC/LSD1 dual-target small molecule inhibitor can increase the expression level of recombinant monoclonal antibodies in CHO cells. • By affecting the acetylation and methylation levels of histones in CHO cells and downregulating HDAC5, the production of recombinant monoclonal antibodies increased. • It provides an effective pathway for applying epigenetic regulation strategies to enhance the expression of recombinant proteins. [ABSTRACT FROM AUTHOR]

Summary Endogenous banana streak virus (eBSV) integrants derived from three distinct species, present in Musa balbisiana (B) but not Musa acuminata (A) banana genomes are able to reconstitute functional episomal viruses causing banana streak disease in interspecific triploid AAB banana hybrids but not in the diploid (BB) parent line, which harbours identical eBSV loci. Here, we investigated the regulation of these eBSV. In‐depth characterization of siRNAs, transcripts and methylation derived from eBSV using Illumina and bisulfite sequencing were carried out on eBSV‐free Musa acuminata AAA plants and BB or AAB banana plants with eBSV. eBSV loci produce low‐abundance transcripts covering most of the viral sequence and generate predominantly 24‐nt siRNAs. siRNA accumulation is restricted to duplicated and inverted viral sequences present in eBSV. Both siRNA‐accumulating and nonaccumulating sequences of eBSV in BB plants are heavily methylated in all three CG, CHG and CHH contexts. Our data suggest that eBSVs are controlled at the epigenetic level in BB diploids. This regulation not only prevents their awakening and systemic infection of the plant but is also probably involved in the inherent resistance of the BB plants to mealybug‐transmitted viral infection. These findings are thus of relevance to other plant resources hosting integrated viruses. [ABSTRACT FROM AUTHOR]

Immune checkpoint inhibitors (ICIs) have transformed cancer treatment by enhancing anti-tumour immune responses, demonstrating significant efficacy in various malignancies, including melanoma. However, over 50% of patients experience limited or no response to ICI therapy. Resistance to ICIs is influenced by a complex interplay of tumour intrinsic and extrinsic factors. This review summarizes current ICIs for melanoma and the factors involved in resistance to the treatment. We also discuss emerging evidence that the microbiota can impact ICI treatment outcomes by modulating tumour biology and anti-tumour immune function. Furthermore, microbiota profiles may offer a non-invasive method for predicting ICI response. Therefore, future research into microbiota manipulation could provide cost-effective strategies to enhance ICI efficacy and improve outcomes for melanoma patients. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) is a common malignant tumor with the third and second highest incidence and mortality rates among various malignant tumors. Despite significant advancements in the present therapy for CRC, the majority of CRC cases feature proficient mismatch repair/microsatellite stability and have no response to immunotherapy. Therefore, the search for new treatment options holds immense importance in the diagnosis and treatment of CRC. In recent years, clinical research on immunotherapy combined with epigenetic therapy has gradually increased, which may bring hope for these patients. This review explores the role of epigenetic regulation in exerting antitumor effects through its action on immune cell function and highlights the potential of certain epigenetic genes that can be used as markers of immunotherapy to predict therapeutic efficacy. We also discuss the application of epigenetic drug sensitization immunotherapy to develop new treatment options combining epigenetic therapy and immunotherapy. [ABSTRACT FROM AUTHOR]

Background: SmithRNAs (Small MITochondrial Highly-transcribed RNAs) are a novel class of small RNA molecules that are encoded in the mitochondrial genome and regulate the expression of nuclear transcripts. Initial evidence for their existence came from the Manila clam Ruditapes philippinarum, where they have been described and whose activity has been biologically validated through RNA injection experiments. Current evidence on the existence of these RNAs in other species is based only on small RNA sequencing. As a preliminary step to characterize smithRNAs across different metazoan lineages, a dedicated, unified, analytical workflow is needed. Results: We propose a novel workflow specifically designed for smithRNAs. Sequence data (from small RNA sequencing) uniquely mapping to the mitochondrial genome are clustered into putative smithRNAs and prefiltered based on their abundance, presence in replicate libraries and 5′ and 3′ transcription boundary conservation. The surviving sequences are subsequently compared to the untranslated regions of nuclear transcripts based on seed pairing, overall match and thermodynamic stability to identify possible targets. Ample collateral information and graphics are produced to help characterize these molecules in the species of choice and guide the operator through the analysis. The workflow was tested on the original Manila clam data. Under basic settings, the results of the original study are largely replicated. The effect of additional parameter customization (clustering threshold, stringency, minimum number of replicates, seed matching) was further evaluated. Conclusions: The study of smithRNAs is still in its infancy and no dedicated analytical workflow is currently available. At its core, the SmithHunter workflow builds over the bioinformatic procedure originally applied to identify candidate smithRNAs in the Manila clam. In fact, this is currently the only evidence for smithRNAs that has been biologically validated and, therefore, the elective starting point for characterizing smithRNAs in other species. The original analysis was readapted using current software implementations and some minor issues were solved. Moreover, the workflow was improved by allowing the customization of different analytical parameters, mostly focusing on stringency and the possibility of accounting for a minimal level of genetic differentiation among samples. [ABSTRACT FROM AUTHOR]

Objective·To analyse the structure of non-canonical polycomb repressive complex 1.6 (PRC1.6) by negative staining and transmission electron microscopy (TEM), and obtain the three-dimensional (3D) profile information of human PRC1.6 heptameric complex. Methods·Seven PRC1.6 components, RNF2, PCGF6, RYBP, L3MBTL2, CBX3, E2F6, and TFDP1, were cloned into the pMLink vector with a 6×His-3×Flag tag at the N-terminus, respectively. The proteins were expressed in Expi293F cells grown in suspension cultures by using transfection with polyethylenimine. The tagged proteins were isolated via affinity purification with anti-DYKDDDDK G1 affinity resin, followed by gel filtration chromatography with Superdex 200 Increase 10/300 GL and glycerol density gradient centrifugation. The components of the PRC1.6 heptameric complex were confirmed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The in vitro ubiquitination activity and nucleosome-binding affinity of the purified heptameric complex were verified by the ubiquitination activity assay and the electrophoretic mobility shift assay (EMSA). The protein samples were stained by uranyl acetate and observed by TEM. The 3D information of the PRC1.6 complex was studied by single particle analysis. To predict the localization of the seven components within the structure model of PRC1.6 complex, the structure models of proteins in Protein Data Bank (PDB) were docked into the electron density map of PRC1.6 complex by using UCSF Chimera software. Results·The PRC1.6 complex with high purity and good homogeneity was obtained by eukaryotic expression, affinity purification, gel filtration chromatography and glycerol density gradient centrifugation, and confirmed as the heptameric complex by LC-MS/MS. The purified proteins showed ubiquitination activity and nucleosome-binding affinity in vitro. The 3D structure of the PRC1.6 heptameric complex with a resolution of 15.2 Å (1 Å=10-10 m) was preliminarily resolved by negative staining, TEM, and single particle analysis. The available structure models of RNF2, PCGF6, RYBP, L3MBTL2, CBX3, and DP1 proteins, as well as the predicted E2F6 structure by AlphaFold2, were docked into the reconstructed density map of PRC1.6 complex. The position of each component in the complex was preliminarily confirmed. Conclusion·The 3D structural model of the human PRC1.6 heptameric complex is obtained by negative staining, TEM, and single particle analysis. [ABSTRACT FROM AUTHOR]

Cellular senescence refers to the stable state of cell cycle arrest in which cells lose the ability of division and proliferation. Various intracellular and extracellular stimuli can induce cell senescence. Senescent cells exhibit multiple hallmarks, such as the upregulation of cell cycle inhibitor proteins p16INK4a and p21Cipl, DNA damage responses, and structural and metabolic alterations. Another major hallmark of senescent cells is that they express and secret a variety of factors, including cytokines, chemokines, growth factors, proteases, and other bioactive molecules, defined as the senescence- associated secretory phenotype (SASP). SASP factors exert multiple biological functions through the cell autonomous autocrine manner or cell non-autonomous paracrine fashion. In this review, we summarize the composition of SASP, and point out its high heterogeneity and dynamics. We then summarize the regulatory mechanisms of SASP at various levels including transcription, post-transcription, translation, post-translational modifications, and epigenetics. Afterwards, we summarize the various biological functions of SASP, including its beneficial effects in tumor suppression, tissue repair, and embryonic development, as well as its detrimental effects in inducing cell senescence, promoting tumor occurrence and development, age-related diseases, and organismal aging. We further discuss the potential applications of the SASP, which overview the senolytic therapy for selectively clearing senescent cells and senomorphic therapy for inhibiting SASP to intervene age and age-related diseases. Finally, we outline several challenges in identifying and detecting senescent cells and SASP factors in vivo, and provide some practical recommendations and new techniques to address these challenges. [ABSTRACT FROM AUTHOR]

The mechanisms underlying the sustained activation of the PI3K/AKT and Wnt/β-catenin pathways mediated by HOTAIR in cervical cancer (CC) have not been extensively described. To address this knowledge gap in the literature, we explored the interactions between these pathways by driving HOTAIR expression levels in HeLa cells. Our findings reveal that HOTAIR is a key regulator in sustaining the activation of both signaling pathways. Specifically, altering HOTAIR expression—either by knockdown or overexpression—significantly influenced the transcriptional activity of the PI3K/AKT and Wnt/β-catenin pathways. Additionally, we discovered that HIF1α directly induces HOTAIR transcription, which in turn leads to the epigenetic silencing of the PTEN promoter via DNMT1. This process leads to the sustained activation of both pathways, highlighting a novel regulatory axis involving HOTAIR and HIF1α in cervical cancer. Our results suggest a new model in which HOTAIR sustains reciprocal activation of the PI3K/AKT and Wnt/β-catenin pathways through the HOTAIR/HIF1α axis, thereby contributing to the oncogenic phenotype of cervical cancer. [ABSTRACT FROM AUTHOR]

The study explores the intricate biochemical mechanisms driving aging and their inferences for prolonged existence and to identify implicit remedial targets for interventions that promote healthier aging. A comprehensive literature investigation was conducted across different databases and search machines to identify material exploration papers, reviews, and studies concentrated on critical biochemical mechanisms driving aging. Data abstraction and synthesis were performed to organize findings into thematic sections, each devoted to a specific biochemical mechanism. The connection of these mechanisms and their relative influence on aging were investigated, and consequences for age-associated conditions and implicit strategies to enhance health span and lifetime were explored. The review highlights the pivotal function of cellular anility, genomic integrity, mitochondrial function, inflammation, genetics, epigenetic regulation, and nutrient seeing in shaping the aging process. Transcriptional processes, including RNA polymerase II extension speed and chromatin structure, are also intertwined in aging. Sirtuins, NAD, and circadian timepieces regulate lifetime and health span, while exercise and nutrition play pivotal functions in maintaining cellular health. Drugs targeting aging pathways and biomarkers for assessing aging processes show capacity. This study provides a comprehensive understanding of the molecular mechanisms underpinning aging and lifetime regulation, stressing the significance of interdisciplinary exploration in addressing the complex challenges of aging. The known biochemical mechanisms offer implicit remedial targets for interventions promoting healthier aging and extended life. Evolving trends and impending directions in longevity research are bandied, and limitations and challenges in deciphering exploration issues into practical interventions are addressed. [ABSTRACT FROM AUTHOR]

Psychostimulants regulate behavioral responses in zebrafish via epigenetic mechanisms. We have previously shown that DNA methylation and histone deacetylase (HDAC) inhibition abolish nicotine-induced conditioned place preference (CPP) but little is known about the role of histone methylation in addictive-like behaviors. To assess the influence of histone methylation on nicotine-CPP, zebrafish were treated with a histone (H3) lysine-9 (K9) dimethyltransferase G9a/GLP inhibitor, BIX-01294 (BIX), which was administered before conditioning sessions. We observed a dual effect of the inhibitor BIX: at high doses inhibited while at low doses potentiated nicotine reward. Transcriptional expression of α6 and α7 subunits of the nicotinic acetylcholine receptor and of G9a, DNA methyl transferase-3, and HDAC-1 was upregulated in zebrafish with positive scores for nicotine-CPP. Changes in relative levels of these mRNA molecules reflected the effects of BIX on nicotine reward. BIX treatment per sé did not affect transcriptional levels of epigenetic enzymes that regulate trimethylation or demethylation of H3. BIX reduced H3K9me2 protein levels in a dose-dependent manner in key structures of the reward pathway. Thus, our findings indicated that different doses of BIX differentially affect nicotine CPP via strong or weak inhibition of G9a/GLP activity. Additionally, we found that the lysine demethylase inhibitor daminozide abolished nicotine-CPP and drug seeking. Our data demonstrate that H3 methylation catalyzed by G9a/GLP is involved in nicotine-CPP induction. Dimethylation of K9 at H3 is an important epigenetic modification that should be considered as a potential therapeutic target to treat nicotine reward and perhaps other drug addictions. [ABSTRACT FROM AUTHOR]

Objective·To analyse the structure of non-canonical polycomb repressive complex 1.6 (PRC1.6) by negative staining and transmission electron microscopy (TEM), and obtain the three-dimensional (3D) profile information of human PRC1.6 heptameric complex.Methods·Seven PRC1.6 components, RNF2, PCGF6, RYBP, L3MBTL2, CBX3, E2F6, and TFDP1, were cloned into the pMLink vector with a 6×His-3×Flag tag at the N-terminus, respectively. The proteins were expressed in Expi293F cells grown in suspension cultures by using transfection with polyethylenimine. The tagged proteins were isolated via affinity purification with anti-DYKDDDDK G1 affinity resin, followed by gel filtration chromatography with Superdex 200 Increase 10/300 GL and glycerol density gradient centrifugation. The components of the PRC1.6 heptameric complex were confirmed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The in vitro ubiquitination activity and nucleosome-binding affinity of the purified heptameric complex were verified by the ubiquitination activity assay and the electrophoretic mobility shift assay (EMSA). The protein samples were stained by uranyl acetate and observed by TEM. The 3D information of the PRC1.6 complex was studied by single particle analysis. To predict the localization of the seven components within the structure model of PRC1.6 complex, the structure models of proteins in Protein Data Bank (PDB) were docked into the electron density map of PRC1.6 complex by using UCSF Chimera software.Results·The PRC1.6 complex with high purity and good homogeneity was obtained by eukaryotic expression, affinity purification, gel filtration chromatography and glycerol density gradient centrifugation, and confirmed as the heptameric complex by LC-MS/MS. The purified proteins showed ubiquitination activity and nucleosome-binding affinity in vitro. The 3D structure of the PRC1.6 heptameric complex with a resolution of 15.2 Å (1 Å=10-10 m) was preliminarily resolved by negative staining, TEM, and single particle analysis. The available structure models of RNF2, PCGF6, RYBP, L3MBTL2, CBX3, and DP1 proteins, as well as the predicted E2F6 structure by AlphaFold2, were docked into the reconstructed density map of PRC1.6 complex. The position of each component in the complex was preliminarily confirmed.Conclusion·The 3D structural model of the human PRC1.6 heptameric complex is obtained by negative staining, TEM, and single particle analysis.

Abstract Colorectal cancer (CRC) is a common malignant tumor with the third and second highest incidence and mortality rates among various malignant tumors. Despite significant advancements in the present therapy for CRC, the majority of CRC cases feature proficient mismatch repair/microsatellite stability and have no response to immunotherapy. Therefore, the search for new treatment options holds immense importance in the diagnosis and treatment of CRC. In recent years, clinical research on immunotherapy combined with epigenetic therapy has gradually increased, which may bring hope for these patients. This review explores the role of epigenetic regulation in exerting antitumor effects through its action on immune cell function and highlights the potential of certain epigenetic genes that can be used as markers of immunotherapy to predict therapeutic efficacy. We also discuss the application of epigenetic drug sensitization immunotherapy to develop new treatment options combining epigenetic therapy and immunotherapy.

Abstract Background SmithRNAs (Small MITochondrial Highly-transcribed RNAs) are a novel class of small RNA molecules that are encoded in the mitochondrial genome and regulate the expression of nuclear transcripts. Initial evidence for their existence came from the Manila clam Ruditapes philippinarum, where they have been described and whose activity has been biologically validated through RNA injection experiments. Current evidence on the existence of these RNAs in other species is based only on small RNA sequencing. As a preliminary step to characterize smithRNAs across different metazoan lineages, a dedicated, unified, analytical workflow is needed. Results We propose a novel workflow specifically designed for smithRNAs. Sequence data (from small RNA sequencing) uniquely mapping to the mitochondrial genome are clustered into putative smithRNAs and prefiltered based on their abundance, presence in replicate libraries and 5′ and 3′ transcription boundary conservation. The surviving sequences are subsequently compared to the untranslated regions of nuclear transcripts based on seed pairing, overall match and thermodynamic stability to identify possible targets. Ample collateral information and graphics are produced to help characterize these molecules in the species of choice and guide the operator through the analysis. The workflow was tested on the original Manila clam data. Under basic settings, the results of the original study are largely replicated. The effect of additional parameter customization (clustering threshold, stringency, minimum number of replicates, seed matching) was further evaluated. Conclusions The study of smithRNAs is still in its infancy and no dedicated analytical workflow is currently available. At its core, the SmithHunter workflow builds over the bioinformatic procedure originally applied to identify candidate smithRNAs in the Manila clam. In fact, this is currently the only evidence for smithRNAs that has been biologically validated and, therefore, the elective starting point for characterizing smithRNAs in other species. The original analysis was readapted using current software implementations and some minor issues were solved. Moreover, the workflow was improved by allowing the customization of different analytical parameters, mostly focusing on stringency and the possibility of accounting for a minimal level of genetic differentiation among samples.

Microalgae often undergo different CO2 experiment in their habitat. To adapt to low CO2, carbon concentrating mechanism (CCM) could be launched in majority of microalgae and CCM are regulated at RNA level are well known. However, epigenetic modifications and their potential regulation of the transcription of masked genes at the genome level in response to CO2 fluctuation remain unclear. Here epigenetic regulation in response to CO2 fluctuation and epigenome-association with phenotypic plasticity of CCM are firstly uncovered in marine microalga Nannochloropsis oceanica IMET1. The result showed that lysine butyrylation (Kbu) and histone H3K9m2 modifications were present in N. oceanica IMET1. Moreover, Kbu modification positively regulated gene expression. In response to CO2 fluctuation, there were 5,438 and 1,106 genes regulated by Kbu and H3K9m2 in Nannochloropsis, respectively. Gained or lost histone methylations were closely associated with activating or repressing gene expressions. Differential modifications were mainly enriched in carbon fixation, photorespiration, photosynthesis, and lipid metabolism etc. Massive genome-wide epigenetic reprogramming was observed after N. oceanica cells shifted from high CO2 to low CO2. Particularly, we firstly noted that the transcription of the key low CO2 responsive carbonic anhydrase (CA5), a key component involved in CCM stress signaling, was potentially regulated by bivalent Kbu-H3K9m2 modifications in microalgae. This study provides novel insights into the relationship between gene transcription and epigenetic modification in Nannochloropsis, which will lay foundation on genetic improvement of CCM at epigenetic level. [ABSTRACT FROM AUTHOR]

The flesh color of pummelo (Citrus maxima) fruits is highly diverse and largely depends on the level of carotenoids, which are beneficial to human health. It is vital to investigate the regulatory network of carotenoid biosynthesis to improve the carotenoid content in pummelo. However, the molecular mechanism underlying carotenoid accumulation in pummelo is not fully understood. In this study, we identified a novel histone methyltransferase gene, CgSDG40, involved in carotenoid regulation by analyzing the flesh transcriptome of typical white-fleshed pummelo, red-fleshed pummelo and extreme-colored F1 hybrids from a segregated pummelo population. Expression of CgSDG40 corresponded to flesh color change and was highly coexpressed with CgPSY1. Interestingly, CgSDG40 and CgPSY1 are located physically adjacent to each other on the chromosome in opposite directions, sharing a partially overlapping promoter region. Subcellular localization analysis indicated that CgSDG40 localizes to the nucleus. Overexpression of CgSDG40 significantly increased the total carotenoid content in citrus calli relative to that in wild type. In addition, expression of CgPSY1 was significantly activated in overexpression lines relative to wild type. Taken together, our findings reveal a novel histone methyltransferase regulator, CgSDG40, involved in the regulation of carotenoid biosynthesis in citrus and provide new strategies for molecular design breeding and genetic improvement of fruit color and nutritional quality.

Abstract Amino acid metabolism plays a pivotal role in tumor microenvironment, influencing various aspects of cancer progression. The metabolic reprogramming of amino acids in tumor cells is intricately linked to protein synthesis, nucleotide synthesis, modulation of signaling pathways, regulation of tumor cell metabolism, maintenance of oxidative stress homeostasis, and epigenetic modifications. Furthermore, the dysregulation of amino acid metabolism also impacts tumor microenvironment and tumor immunity. Amino acids can act as signaling molecules that modulate immune cell function and immune tolerance within the tumor microenvironment, reshaping the anti-tumor immune response and promoting immune evasion by cancer cells. Moreover, amino acid metabolism can influence the behavior of stromal cells, such as cancer-associated fibroblasts, regulate ECM remodeling and promote angiogenesis, thereby facilitating tumor growth and metastasis. Understanding the intricate interplay between amino acid metabolism and the tumor microenvironment is of crucial significance. Expanding our knowledge of the multifaceted roles of amino acid metabolism in tumor microenvironment holds significant promise for the development of more effective cancer therapies aimed at disrupting the metabolic dependencies of cancer cells and modulating the tumor microenvironment to enhance anti-tumor immune responses and inhibit tumor progression.

Abstract Background Gastrointestinal malignancies encompass a diverse group of cancers that pose significant challenges to global health. The major histocompatibility complex (MHC) plays a pivotal role in immune surveillance, orchestrating the recognition and elimination of tumor cells by the immune system. However, the intricate regulation of MHC gene expression is susceptible to dynamic epigenetic modification, which can influence functionality and pathological outcomes. Main body By understanding the epigenetic alterations that drive MHC downregulation, insights are gained into the molecular mechanisms underlying immune escape, tumor progression, and immunotherapy resistance. This systematic review examines the current literature on epigenetic mechanisms that contribute to MHC deregulation in esophageal, gastric, pancreatic, hepatic and colorectal malignancies. Potential clinical implications are discussed of targeting aberrant epigenetic modifications to restore MHC expression and 0 the effectiveness of immunotherapeutic interventions. Conclusion The integration of epigenetic-targeted therapies with immunotherapies holds great potential for improving clinical outcomes in patients with gastrointestinal malignancies and represents a compelling avenue for future research and therapeutic development.

In a study of DNA methylation changes in melatonin-deficient rice mutants, mutant plants showed premature leaf senescence during grain-filling and reduced grain yield. Melatonin deficiency led to transcriptional reprogramming, especially of genes involved in chlorophyll and carbon metabolism, redox regulation, and transcriptional regulation, during dark-induced leaf senescence. Hypomethylation of mCG and mCHG in the melatonin-deficient rice mutants was associated with the expression change of both protein-coding genes and transposable element-related genes. Changes in gene expression and DNA methylation in the melatonin-deficient mutants were compensated by exogenous application of melatonin. A decreased S-adenosyl-L-methionine level may have contributed to the DNA methylation variations in rice mutants of melatonin deficiency under dark conditions.

High-quality seeds provide valuable nutrients to human society and ensure successful seedling establishment. During maturation, seeds accumulate storage compounds that are required to sustain seedling growth during germination. This review focuses on the epigenetic repression of the embryonic and seed maturation programs in seedlings. We begin with an extensive overview of mutants affecting these processes, illustrating the roles of core proteins and accessory components in the epigenetic machinery by comparing mutants at both phenotypic and molecular levels. We highlight how omics assays help uncover target-specific functional specialization and coordination among various epigenetic mechanisms. Furthermore, we provide an in-depth discussion on the Seed dormancy 4 (Sdr4) transcriptional corepressor family, comparing and contrasting their regulation of seed germination in the dicotyledonous species Arabidopsis and two monocotyledonous crops, rice and wheat. Finally, we compare the similarities in the activation and repression of the embryonic and seed maturation programs through a shared set of cis-regulatory elements and discuss the challenges in applying knowledge largely gained in model species to crops. [ABSTRACT FROM AUTHOR]

Summary: The regulatory mechanisms of anthocyanin biosynthesis have been well documented at the transcriptional and translational levels. By contrast, how anthocyanin biosynthesis is epigenetically regulated remains largely unknown.In this study, we employed genetic, molecular biology, and chromatin immunoprecipitation‐quantitative polymerase chain reaction assays to identify a regulatory module essential for repressing the expression of genes involved in anthocyanin biosynthesis through chromatin remodeling.We found that SILENCING DEFECTIVE 2 (SDE2), which was previously identified as a negative regulator for sucrose‐induced anthocyanin accumulation in Arabidopsis, is cleaved into N‐terminal SDE2‐UBL and C‐terminal SDE2‐C fragments at the first diglycine motif, and the cleaved SDE2‐C, which can fully complement the sde2 mutant, is localized in the nucleus and physically interacts with LIKE HETEROCHROMATIN PROTEIN 1 (LHP1) in vitro and in vivo. Genetic analyses showed that both SDE2 and LHP1 act as negative factors for anthocyanin biosynthesis. Consistently, immunoblot analysis revealed that the level of LHP1‐bound histone H3 lysine 27 trimethylation (H3K27me3) significantly decreases in sde2 and lhp1 mutants, compared to wild‐type (WT). In addition, we found that sugar can induce expression of SDE2 and LHP1, and enhance the level of the nucleus‐localized SDE2‐C.Taken together, our data suggest that the SDE2‐C‐LHP1 module is required for repression of gene expression through H3K27me3 modification during sugar‐induced anthocyanin biosynthesis in Arabidopsis thaliana. See also the Commentary on this article by LaFountain, 243: 1287–1289. [ABSTRACT FROM AUTHOR]

Repetitive sequences play an indispensable role in gene expression, transcriptional regulation, and chromosome arrangements through trans and cis regulation. In this review, focusing on recent advances, we summarize the epigenetic regulatory mechanisms of repetitive sequences in embryonic stem cells. We aim to bridge the knowledge gap by discussing DNA damage repair pathway choices on repetitive sequences and summarizing the significance of chromatin organization on repetitive sequences in response to DNA damage. By consolidating these insights, we underscore the critical relationship between the stability of repetitive sequences and early embryonic development, seeking to provide a deeper understanding of repetitive sequence stability and setting the stage for further research and potential therapeutic strategies in developmental biology and regenerative medicine. [ABSTRACT FROM AUTHOR]

The epigenetic layer of regulation has become increasingly relevant in the research focused on tumor suppressors. KLF4 is a well-described zinc-finger transcription factor, mainly known for its role in the acquisition of cell pluripotency. Here we report and describe the most relevant epigenetic regulation mechanisms that affect KLF4 expression in tumors. CpG island methylation emerges as the most common mechanism in several tumors including lung adenocarcinoma, hepatocellular carcinoma, non-Hodgkin lymphomas, among others. Further layers of regulation represented by histone methylation and acetylation and by non-coding RNAs are described. Overall, KLF4 emerges as a crucial target in the fight against cancer. [ABSTRACT FROM AUTHOR]

The effects of HIF1A knockdown by RNA interference on the histone H3K9 methylation in human umbilical cord mesenchymal stromal cells in vitro under conditions of 24-h exposure to hypoxia (1% O2) were studied. Evaluation of transcriptional activity of genes involved in the regulation of H3K9 methylation (KDM3A, KDM4A, and EHMT2) and the cytofluorimetric analysis of the expression of the corresponding antigens and H3K9 methylation level demonstrated a pronounced stimulating effect of hypoxic exposure. Moreover, the expression of KDM4A and EHMT2 was regulated by HIF1A-mediated mechanism, unlike KDM3A; the level of the corresponding proteins depended on HIF1A. In addition, the HIF-1-dependent regulation of KDM3A, KDM4A, and EHMT2/G9a, and directly the H3K9 methylation level in mesenchymal stromal cells also took place under normoxia conditions. [ABSTRACT FROM AUTHOR]

Medicinal and aromatic plants (MAPs) are well known for their valuable secondary metabolites and diverse phytochemicals responsible for a plethora of medicinal properties such as antimicrobial, antioxidant, anti-inflammatory, anticancerous, and analgesic activities, making them essential for various industries. Therefore, this significant market demand has led to the need to improve the quality and quantity of secondary metabolites and thus develop high-quality commercial products. In this context, polyploidization is considered a sound contemporary approach that produces new genotypes, leading to the overexpression of genes involved in biosynthesizing crucial metabolites. Enhanced natural metabolite production increases the biological activities of plant extracts along with enhanced tolerance against abiotic and biotic stresses to achieve homogeneity. This improvisation in the quality and quantity of plant secondary metabolites can maximize the medicinal value of the plants. Therefore, this mini-review aims to explore the importance of enhancing biological activity in medicinal plants, summarize the progress of synthetic polyploidization as a breeding tool in MAP species, and elucidate how this technique plays an important role in improving medicinal values. This breeding strategy could significantly advance future research and industrial applications by inducing superior genotypes with enhanced genomic complexity and improving traits like increased biomass, stress tolerance, and novel biochemical pathways. So, it can be concluded that in vitro synthetic polyploidization can be an effective tool for promoting the production of more distinctive genotypes with immense medicinal properties for a variety of commercial and pharmaceutical purposes. [ABSTRACT FROM AUTHOR]

Intracellular free Zn2+ ([Zn2+]i) is less than 1-nM in cardiomyocytes and its regulation is performed with Zn2+-transporters. However, the roles of Zn2+-transporters in cardiomyocytes are not defined exactly yet. Here, we aimed to examine the role of an overexpression and subcellular localization of a ZnT6 in insulin-resistance mimic H9c2 cardiomyoblasts (IR-cells; 50-μM palmitic acid for 24-h incubation). We used both IR-cells and ZnT6-overexpressed (ZnT6OE) cells in comparison to those of H9c2 cells (CON-cells). The IR-cells have higher ZnT6-protein levels than CON-cells while this level was similar to those of ZnT6OE-cells. The [Zn2+]i in IR-cells was increased significantly and mitochondrial localization of ZnT6 was demonstrated in these cells by using confocal microscopy visualization. Furthermore, electron microscopy analysis demonstrated abnormal morphological appearance in both IR-cells and ZnT6OE-cells characterized by irregular mitochondrion cristae and condensed and dilated cisterna in the sarcoplasmic reticulum. Mitochondria were similarly depolarized in both IR-cells and ZnT6OE-cells. The protein expression level of a mitofusin protein MFN2 in the IR-cells was decreased, significantly, whereas, it was found significantly upregulated in both ZnT6-OE-cells and IR-incubated ZnT6OE-cells, which demonstrates the role of ZnT6-overexpression but not IR. Additionally, the total protein level of a mitochondrial fission protein, dynamin-related protein 1, DRP1 was found to be increased over 1.5-fold in IR-cells while this increase was found to be higher in the ZnT6OE-cells than those of IR-cells, demonstrating an additional effect on IR-increase. ZnT6-overexpression induced also significant increases in K-acetylation, trimethylation of histone H3 lysine27, and mono-methylation of histone H3 lysine36, in a similar manner to those of IR-cells. Overall, our data point out an important contribution of ZnT6-overexpression to IR-induced cellular changes, such as alteration in mitochondria function and activation of epigenetic modifications. [ABSTRACT FROM AUTHOR]

P-element-induced wimpy testis-interacting RNAs (piRNAs), a class of small noncoding RNAs with about 24–32 nucleotides, often interact with PIWI proteins to form a piRNA/PIWI complex that could influence spermiogenesis, transposon silencing, epigenetic regulation, etc. PIWI proteins have a highly conserved function in a variety of species and are usually expressed in germ cells. However, increasing evidence has revealed the important role of the piRNA/PIWI complex in the occurrence and prognosis of various human diseases and suggests its potential application in the diagnosis and treatment of related diseases, becoming a prominent marker for these human diseases. Recent studies have confirmed that piRNA/PIWI complexes or piRNAs are abnormally expressed in some viral infections, effecting disease progression and viral replication. In this study, we reviewed the association between the piRNA/PIWI complex and several human disease-associated viruses, including human papillomavirus, human immunodeficiency virus, human rhinovirus, severe acute respiratory syndrome coronavirus 2, respiratory syncytial virus, and herpes simplex virus type 1. [ABSTRACT FROM AUTHOR]

Macrophages are versatile immune cells with remarkable plasticity, enabling them to adapt to diverse tissue microenvironments and perform various functions. Traditionally categorized into classically activated (M1) and alternatively activated (M2) phenotypes, recent advances have revealed a spectrum of macrophage activation states that extend beyond this dichotomy. The complex interplay of signaling pathways, transcriptional regulators, and epigenetic modifications orchestrates macrophage polarization, allowing them to respond to various stimuli dynamically. Here, we provide a comprehensive overview of the signaling cascades governing macrophage plasticity, focusing on the roles of Toll‐like receptors, signal transducer and activator of transcription proteins, nuclear receptors, and microRNAs. We also discuss the emerging concepts of macrophage metabolic reprogramming and trained immunity, contributing to their functional adaptability. Macrophage plasticity plays a pivotal role in tissue repair and regeneration, with macrophages coordinating inflammation, angiogenesis, and matrix remodeling to restore tissue homeostasis. By harnessing the potential of macrophage plasticity, novel therapeutic strategies targeting macrophage polarization could be developed for various diseases, including chronic wounds, fibrotic disorders, and inflammatory conditions. Ultimately, a deeper understanding of the molecular mechanisms underpinning macrophage plasticity will pave the way for innovative regenerative medicine and tissue engineering approaches. [ABSTRACT FROM AUTHOR]

To tackle misdiagnosis in lung cancer screening with low‐dose computed tomography (LDCT), we aimed to compile a genome atlas for differentiating benign, preinvasive, and invasive lung nodules and characterize their molecular pathogenesis. We collected 432 lung nodule tissue samples from Chinese patients, spanning benign, atypical adenomatous hyperplasia (AAH), adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA), and invasive adenocarcinoma (IA). We performed comprehensive sequencing, examining somatic variants, gene expressions, and methylation levels. Our findings uncovered EGFR and TP53 mutations as key drivers in ‐ early lung cancer development, with EGFR mutation frequency increasing with disease progression. Both EGFR mutations and EGF/EGFR hypo‐methylation activated the EGFR pathway, fueling cancer growth. Transcriptome analysis identified four lung nodule subtypes (G1‐4) with distinct molecular features and immune cell infiltrations: EGFR‐driven G1, EGFR/TP53 co‐mutation G2, inflamed G3, stem‐like G4. Estrogen/androgen response was associated with the EGFR pathway, proposing a new therapy combining tyrosine kinase inhibitors with antiestrogens. Preinvasive nodules exhibited stem cell pathway enrichment, potentially hindering invasion. Epigenetic regulation of various genes was essential for lung cancer initiation and development. This study provides insights into the molecular mechanism of neoplastic progression and identifies potential diagnostic biomarkers and therapeutic targets for lung cancer. [ABSTRACT FROM AUTHOR]

Amino acid metabolism plays a pivotal role in tumor microenvironment, influencing various aspects of cancer progression. The metabolic reprogramming of amino acids in tumor cells is intricately linked to protein synthesis, nucleotide synthesis, modulation of signaling pathways, regulation of tumor cell metabolism, maintenance of oxidative stress homeostasis, and epigenetic modifications. Furthermore, the dysregulation of amino acid metabolism also impacts tumor microenvironment and tumor immunity. Amino acids can act as signaling molecules that modulate immune cell function and immune tolerance within the tumor microenvironment, reshaping the anti-tumor immune response and promoting immune evasion by cancer cells. Moreover, amino acid metabolism can influence the behavior of stromal cells, such as cancer-associated fibroblasts, regulate ECM remodeling and promote angiogenesis, thereby facilitating tumor growth and metastasis. Understanding the intricate interplay between amino acid metabolism and the tumor microenvironment is of crucial significance. Expanding our knowledge of the multifaceted roles of amino acid metabolism in tumor microenvironment holds significant promise for the development of more effective cancer therapies aimed at disrupting the metabolic dependencies of cancer cells and modulating the tumor microenvironment to enhance anti-tumor immune responses and inhibit tumor progression. [ABSTRACT FROM AUTHOR]

In eukaryotes, histone acetylation and deacetylation play an important role in the regulation of gene expression. Histone acetylation levels are reversibly regulated by histone acetyltransferases (HATs) and histone deacetylases (HDACs). Increasing evidence highlights histone acetylation plays essential roles in the regulation of gene expression in plant response to environmental stress. In this review, we discussed the recent advance of histone acetylation in the regulation of abiotic stress responses including temperature, light, salt and drought stress. This information will contribute to our understanding of how plants adapt to environmental changes. As the mechanisms of epigenetic regulation are conserved in many plants, research in this field has potential applications in improvement of agricultural productivity. [ABSTRACT FROM AUTHOR]

Aberrant DNA methylation is a hallmark of many cancer types. Despite our knowledge of epigenetic and transcriptomic alterations in lung adenocarcinoma (LUAD), we lack robust multi‐modal molecular classifications for patient stratification. This is partly because the impact of epigenetic alterations on lung cancer development and progression is still not fully understood. To that end, we identified disease‐associated processes under epigenetic regulation in LUAD. We performed a genome‐wide expression‐methylation Quantitative Trait Loci (emQTL) analysis by integrating DNA methylation and gene expression data from 453 patients in the TCGA cohort. Using a community detection algorithm, we identified distinct communities of CpG‐gene associations with diverse biological processes. Interestingly, we identified a community linked to hormone response and lipid metabolism; the identified CpGs in this community were enriched in enhancer regions and binding regions of transcription factors such as FOXA1/2, GRHL2, HNF1B, AR, and ESR1. Furthermore, the CpGs were connected to their associated genes through chromatin interaction loops. These findings suggest that the expression of genes involved in hormone response and lipid metabolism in LUAD is epigenetically regulated through DNA methylation and enhancer‐promoter interactions. By applying consensus clustering on the integrated expression‐methylation pattern of the emQTL‐genes and CpGs linked to hormone response and lipid metabolism, we further identified subclasses of patients with distinct prognoses. This novel patient stratification was validated in an independent patient cohort of 135 patients and showed increased prognostic significance compared to previously defined molecular subtypes. [ABSTRACT FROM AUTHOR]

The epigenetic machinery has received extensive attention due to its involvement in plant growth, development, and adaptation to environmental changes. Recent studies often highlight the epigenetic regulatory network by discussing various epigenetic mutants across various plant species. However, a systemic understanding of essential epigenetic regulatory mechanisms remains limited due to a lack of representative mutants involved in multiple biological processes. Colorless Non-ripening (Cnr), a spontaneous epimutant isolated from a commercial population, was initially characterized for its role in fruit ripening regulation. Cnr fruits exhibit an immature phenotype with yellow skin, attributed to hypermethylation of the SQUAMOSA PROMOTER BINDING PROTEIN-LIKECNR (SlSPL-CNR) promoter, resulting in the repression of gene expression. In addition to DNA methylation, this process also involves histone modification and microRNA, integrating multiple epigenetic regulatory factors. Interestingly, knockout mutants of SlSPL-CNR display phenotypical distinctions from Cnr in fruit ripening, indicating complex genetic and epigenetic control over the nonripening phenotype in Cnr fruits. Accumulating evidence suggests that Cnr epimutation is pleiotropic, participating in various biological processes such as Cd stress, Fe deficiency, vivipary, and cell death. Therefore, the Cnr epimutant serve as an excellent model for unveiling how epigenetic mechanisms are involved in diverse biological processes. This review paper focuses on recent research advances regarding the Cnr epimutant, delving into its complex genetic and epigenetic regulatory mechanisms, with the aim of enhancing our understanding and facilitating the development of high-quality, high-yield crops through epigenetic modification. [ABSTRACT FROM AUTHOR]

The most prevalent primary brain tumors in adults are gliomas. In addition to insufficient therapeutic alternatives, gliomas are fatal mostly due to the rapid proliferation and continuous infiltration of tumor cells into the surrounding healthy brain tissue. According to a growing body of research, aerobic glycolysis, or the Warburg effect, promotes glioma development because gliomas are heterogeneous cancers that undergo metabolic reprogramming. Therefore, addressing the Warburg effect might be a useful therapeutic strategy for treating cancer. Lactate plays a critical role in reprogramming energy metabolism, allowing cells to rapidly access large amounts of energy. Lactate, a byproduct of glycolysis, is therefore present in rapidly proliferating cells and tumors. In addition to the protumorigenesis pathways of lactate synthesis, circulation, and consumption, lactate-induced lactylation has been identified in recent investigations. Lactate plays crucial roles in modulating immune processes, maintaining homeostasis, and promoting metabolic reprogramming in tumors, which are processes regulated by the lactate-induced lactylation of the lysine residues of histones. In this paper, we discuss the discovery and effects of lactylation, review the published studies on how protein lactylation influences cancer growth and further explore novel treatment approaches to achieve improved antitumor effects by targeting lactylation. These findings could lead to a new approach and guidance for improving the prognosis of patients with gliomas. [ABSTRACT FROM AUTHOR]

The epidermis of the skin provides a barrier between the organism and the external environment. It is constantly subjected to physical and chemical insults, and thus susceptible to wounding and to neoplastic transformation. Long-lasting epigenetic modifications in epidermal stem cells are now shown to link responses to skin injuries with cell priming for carcinoma development, through regulation of histone H2A ubiquitylation. [ABSTRACT FROM AUTHOR]

Duplicated genes provide the opportunity for evolutionary novelty and adaptive divergence. In many cases, having more gene copies increases gene expression, which might facilitate adaptation to stressful or novel environments. Conversely, overexpression or misexpression of duplicated genes can be detrimental and subject to negative selection. In this scenario, newly duplicate genes may evade purifying selection if they are epigenetically silenced, at least temporarily, leading them to persist in populations as copy number variations (CNVs). In animals and plants, younger gene duplicates tend to have higher levels of DNA methylation and lower levels of gene expression, suggesting epigenetic regulation could promote the retention of gene duplications via expression repression or silencing. Here, we test the hypothesis that DNA methylation variation coincides with young duplicate genes that are segregating as CNVs in six populations of the three‐spined stickleback that span a salinity gradient from 4 to 30 PSU. Using reduced‐representation bisulfite sequencing, we found DNA methylation and CNV differentiation outliers rarely overlapped. Whereas lineage‐specific genes and young duplicates were found to be highly methylated, just two gene CNVs showed a significant association between promoter methylation level and copy number, suggesting that DNA methylation might not interact with CNVs in our dataset. If most new duplications are regulated for dosage by epigenetic mechanisms, our results do not support a strong contribution from DNA methylation soon after duplication. Instead, our results are consistent with a preference to duplicate genes that are already highly methylated. [ABSTRACT FROM AUTHOR]

Objective: DNA methylation as intensively studied epigenetic regulatory mechanism exerts pleiotropic effects on dental‐derived mesenchymal stem cells (DMSCs). DMSCs have self‐renewal and multidifferentiation potential. Here, this review aims at summarizing the research status about application of DMSCs in tissue engineering and clarifying the roles of DNA methylation in influencing the functions of DMSCs, with expectation of paving the way for its in‐depth exploration in tissue engineering. Method: The current research status about influence of DNA methylation in DMSCs was acquired by MEDLINE (through PubMed) and Web of Science using the keywords 'DNA methylation', 'dental‐derived mesenchymal stem cells', 'dental pulp stem cells', 'periodontal ligament stem cells', 'dental follicle stem cells', 'stem cells from the apical papilla', 'stem cells from human exfoliated deciduous teeth', and 'gingival‐derived mesenchymal stem cells'. Results: This review indicates DNA methylation affects DMSCs' differentiation and function through inhibiting or enhancing the expression of specific gene resulted by DNA methylation‐related genes or relevant inhibitors. Conclusion: DNA methylation can influence DMSCs in aspects of osteogenesis, adipogenesis, immunomodulatory function, and so on. Yet, the present studies about DNA methylation in DMSCs commonly focus on dental pulp stem cells (DPSCs) and periodontal ligament stem cells (PDLSCs). Little has been reported for other DMSCs. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) constitutes a multifactorial neurodegenerative pathology characterized by cognitive deterioration, personality alterations, and behavioral shifts. The ongoing brain impairment process poses significant challenges for therapeutic interventions due to activating multiple neurotoxic pathways. Current pharmacological interventions have shown limited efficacy and are associated with significant side effects. Approaches focusing on the early interference with disease pathways, before activation of broad neurotoxic processes, could be promising to slow down symptomatic progression of the disease. Curcumin—an integral component of traditional medicine in numerous cultures worldwide—has garnered interest as a promising AD treatment. Current research indicates that curcumin may exhibit therapeutic potential in neurodegenerative pathologies, attributed to its potent anti‐inflammatory and antioxidant properties. Additionally, curcumin and its derivatives have demonstrated an ability to modulate cellular pathways via epigenetic mechanisms. This article aims to raise awareness of the neuroprotective properties of curcuminoids that could provide therapeutic benefits in AD. The paper provides a comprehensive overview of the neuroprotective efficacy of curcumin against signaling pathways that could be involved in AD and summarizes recent evidence of the biological efficiency of curcumins in vivo. [ABSTRACT FROM AUTHOR]

Background: Gastrointestinal malignancies encompass a diverse group of cancers that pose significant challenges to global health. The major histocompatibility complex (MHC) plays a pivotal role in immune surveillance, orchestrating the recognition and elimination of tumor cells by the immune system. However, the intricate regulation of MHC gene expression is susceptible to dynamic epigenetic modification, which can influence functionality and pathological outcomes. Main body: By understanding the epigenetic alterations that drive MHC downregulation, insights are gained into the molecular mechanisms underlying immune escape, tumor progression, and immunotherapy resistance. This systematic review examines the current literature on epigenetic mechanisms that contribute to MHC deregulation in esophageal, gastric, pancreatic, hepatic and colorectal malignancies. Potential clinical implications are discussed of targeting aberrant epigenetic modifications to restore MHC expression and 0 the effectiveness of immunotherapeutic interventions. Conclusion: The integration of epigenetic-targeted therapies with immunotherapies holds great potential for improving clinical outcomes in patients with gastrointestinal malignancies and represents a compelling avenue for future research and therapeutic development. [ABSTRACT FROM AUTHOR]