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Polycomb proteins are a fundamental repressive system that plays crucial developmental roles by orchestrating cell-type-specific transcription programs that govern cell identity. Direct alterations of Polycomb activity are indeed implicated in human pathologies, including developmental disorders and cancer. General Polycomb repression is coordinated by three distinct activities that regulate the deposition of two histone post-translational modifications: tri-methylation of histone H3 lysine 27 (H3K27me3) and histone H2A at lysine 119 (H2AK119ub1). These activities exist in large and heterogeneous multiprotein ensembles consisting of common enzymatic cores regulated by heterogeneous non-catalytic modules composed of a large number of accessory proteins with diverse biochemical properties. Here, we have analyzed the current molecular knowledge, focusing on the functional interaction between the core enzymatic activities and their regulation mediated by distinct accessory modules. This provides a comprehensive analysis of the molecular details that control the establishment and maintenance of Polycomb repression, examining their underlying coordination and highlighting missing information and emerging new features of Polycomb-mediated transcriptional control. The Polycomb machinery is a major repressive system essential for development, stem cell, and tissue homeostasis directly involved in several human pathologies. Tamburri et al. explored the molecular complexity by which different core enzymatic activities and regulatory modules coordinate to establish and maintain repressive domains to control cell transcriptional identities. [ABSTRACT FROM AUTHOR]

Summary Chromatin immunoprecipitation and sequencing (vs ChIP‐seq) is an essential tool for epigenetic and molecular genetic studies. Although being routinely used, ChIP‐seq is expensive, requires grams of plant materials, and is challenging for samples that enrich fatty acids such as seeds. Here, we developed an Ultrasensitive Plant ChIP‐seq (UP‐ChIP) method based on native ChIP‐seq combined with Tn5 tagmentation‐based library construction strategy. UP‐ChIP is generally applicable for profiling both histone modification and Pol II in a wide range of plant samples, such as a single Arabidopsis seedling, a few Arabidopsis seeds, and sorted nuclei. Compared with conventional ChIP‐seq, UP‐ChIP is much less labor intensive and only consumes 1 μg of antibody and 10 μl of Protein‐A/G conjugated beads for each IP and can work effectively with the amount of starting material down to a few milligrams. By performing UP‐ChIP in various conditions and genotypes, we showed that UP‐ChIP is highly reliable, sensitive, and quantitative for studying histone modifications. Detailed UP‐ChIP protocol is provided. We recommend UP‐ChIP as an alternative to traditional ChIP‐seq for profiling histone modifications and Pol II, offering the advantages of reduced labor intensity, decreased costs, and low‐sample input. [ABSTRACT FROM AUTHOR]

The progressive degeneration of motor neurons in amyotrophic lateral sclerosis (ALS) is accompanied by the formation of a broad array of cytoplasmic and nuclear neuronal inclusions (protein aggregates) largely containing RNA-binding proteins such as TAR DNA-binding protein 43 (TDP-43) or fused in sarcoma/translocated in liposarcoma (FUS/TLS). This process is driven by a liquid-to-solid phase separation generally from proteins in membrane-less organelles giving rise to pathological biomolecular condensates. The formation of these protein aggregates suggests a fundamental alteration in the mRNA expression or the levels of the proteins involved. Considering the role of the epigenome in gene expression, alterations in DNA methylation, histone modifications, chromatin remodeling, non-coding RNAs, and RNA modifications become highly relevant to understanding how this pathological process takes effect. In this review, we explore the evidence that links epigenetic mechanisms with the formation of protein aggregates in ALS. We propose that a greater understanding of the role of the epigenome and how this inter-relates with the formation of pathological LLPS in ALS will provide an attractive therapeutic target. [ABSTRACT FROM AUTHOR]

Plant hormones, pivotal regulators of plant growth, development, and response to environmental cues, have recently emerged as central modulators of epigenetic processes governing gene expression and phenotypic plasticity. This review addresses the complex interplay between plant hormones and epigenetic mechanisms, highlighting the diverse methodologies that have been harnessed to decipher these intricate relationships. We present a comprehensive overview to understand how phytohormones orchestrate epigenetic modifications, shaping plant adaptation and survival strategies. Conversely, we explore how epigenetic regulators ensure hormonal balance and regulate the signalling pathways of key plant hormones. Furthermore, our investigation includes a search for novel genes that are regulated by plant hormones under the control of epigenetic processes. Our review offers a contemporary overview of the epigenetic–plant hormone crosstalk, emphasizing its significance in plant growth, development, and potential agronomical applications. [ABSTRACT FROM AUTHOR]

During the development of multicellular organisms and cell differentiation, the chromatin structure in the cell nucleus undergoes extensive changes, and the nucleosome structure is formed by a combination of various histone variants. Histone variants with diverse posttranslational modifications are known to play crucial roles in different regulatory functions. We have previously reported that H3t, a testis-specific histone variant, is essential for spermatogenesis. To elucidate the function of this chromatin molecule in vivo, we generated knock-in mice with a FLAG tag attached to the carboxyl terminus of H3t. In the present study, we evaluated the utility of the generated knock-in mice and comprehensively analyzed posttranslational modifications of canonical H3 and H3t using mass spectrometry. Herein, we found that H3t-FLAG was incorporated into spermatogonia and meiotic cells in the testes, as evidenced by immunostaining of testicular tissue. According to the mass spectrometry analysis, the overall pattern of H3t-FLAG posttranslational modification was comparable to that of the control H3, while the relative abundances of certain specific modifications differed between H3t-FLAG and the control bulk H3. The generated knock-in mice could be valuable for analyzing the function of histone variants in vivo. [ABSTRACT FROM AUTHOR]

Impaired wound healing is one of the main clinical complications of type 2 diabetes (T2D) and a major cause of lower limb amputation. Diabetic wounds exhibit a sustained inflammatory state, and reducing inflammation is crucial to diabetic wounds management. Macrophages are key regulators in wound healing, and their dysfunction would cause exacerbated inflammation and poor healing in diabetic wounds. Gene regulation caused by histone modifications can affect macrophage phenotype and function during diabetic wound healing. Recent studies have revealed that targeting histone-modifying enzymes in a local, macrophage-specific manner can reduce inflammatory responses and improve diabetic wound healing. This article will review the significance of macrophage phenotype and function in wound healing, as well as illustrate how histone modifications affect macrophage polarization in diabetic wounds. Targeting macrophage phenotype with histone-modifying enzymes may provide novel therapeutic strategies for the treatment of diabetic wound healing. [ABSTRACT FROM AUTHOR]

Gastrointestinal tumors, the second leading cause of human mortality, are characterized by their association with inflammation. Currently, progress in the early diagnosis and effective treatment of gastrointestinal tumors is limited. Recent whole‐genome analyses have underscored their profound heterogeneity and extensive genetic and epigenetic reprogramming. Epigenetic reprogramming pertains to dynamic and hereditable alterations in epigenetic patterns, devoid of concurrent modifications in the underlying DNA sequence. Common epigenetic modifications encompass DNA methylation, histone modifications, noncoding RNA, RNA modifications, and chromatin remodeling. These modifications possess the potential to invoke or suppress a multitude of genes associated with cancer, thereby governing the establishment of chromatin configurations characterized by diverse levels of accessibility. This intricate interplay assumes a pivotal and indispensable role in governing the commencement and advancement of gastrointestinal cancer. This article focuses on the impact of epigenetic reprogramming in the initiation and progression of gastric cancer, esophageal cancer, and colorectal cancer, as well as other uncommon gastrointestinal tumors. We elucidate the epigenetic landscape of gastrointestinal tumors, encompassing DNA methylation, histone modifications, chromatin remodeling, and their interrelationships. Besides, this review summarizes the potential diagnostic, therapeutic, and prognostic targets in epigenetic reprogramming, with the aim of assisting clinical treatment strategies. [ABSTRACT FROM AUTHOR]

Simple Summary: Angiogenesis is a crucial process in the progression and metastasis of melanoma. Recent research has highlighted the significant role of epigenetic modifications in regulating angiogenesis. This review comprehensively examines the current understanding of how epigenetic mechanisms, including DNA methylation, histone modifications, and non-coding RNAs, influence angiogenic pathways in melanoma, with some important therapeutic approaches. Angiogenesis, the formation of new blood vessels from pre-existing ones, is a crucial process in the progression and metastasis of melanoma. Recent research has highlighted the significant role of epigenetic modifications in regulating angiogenesis. This review comprehensively examines the current understanding of how epigenetic mechanisms, including DNA methylation, histone modifications, and non-coding RNAs, influence angiogenic pathways in melanoma. DNA methylation, a key epigenetic modification, can silence angiogenesis inhibitors such as thrombospondin-1 and TIMP3 while promoting pro-angiogenic factors like vascular endothelial growth factor (VEGF). Histone modifications, including methylation and acetylation, also play a pivotal role in regulating the expression of angiogenesis-related genes. For instance, the acetylation of histones H3 and H4 is associated with the upregulation of pro-angiogenic genes, whereas histone methylation patterns can either enhance or repress angiogenic signals, depending on the specific histone mark and context. Non-coding RNAs, particularly microRNAs (miRNAs) further modulate angiogenesis. miRNAs, such as miR-210, have been identified as key regulators, with miR-9 promoting angiogenesis by targeting E-cadherin and enhancing the expression of VEGF. This review also discusses the therapeutic potential of targeting epigenetic modifications to inhibit angiogenesis in melanoma. Epigenetic drugs, such as DNA methyltransferase inhibitors (e.g., 5-azacytidine) and histone deacetylase inhibitors (e.g., Vorinostat), have shown promise in preclinical models by reactivating angiogenesis inhibitors and downregulating pro-angiogenic factors. Moreover, the modulation of miRNAs and lncRNAs presents a novel approach for anti-angiogenic therapy. [ABSTRACT FROM AUTHOR]

Rare neurological diseases include a vast group of heterogenous syndromes with primary impairment(s) in the peripheral and/or central nervous systems. Such rare disorders may have overlapping phenotypes, despite their distinct genetic etiology. One unique aspect of rare neurological diseases is their potential common association with altered epigenetic mechanisms. Epigenetic mechanisms include regulatory processes that control gene expression and cellular phenotype without changing the composition of the corresponding DNA sequences. Epigenetic factors include three types of proteins, the "readers, writers, and erasers" of DNA and DNA-bound proteins. Thus, epigenetic impairments of many neurological diseases may contribute to their pathology and manifested phenotypes. Here, we aim to provide a comprehensive review on the general etiology of selected rare neurological diseases, that include Rett Syndrome, Prader-Willi Syndrome, Rubinstein-Taybi Syndrome, Huntington's disease, and Angelman syndrome, with respect to their associated aberrant epigenetic mechanisms. [ABSTRACT FROM AUTHOR]

Simple Summary: Epigenetics plays a significant role in understanding depression, which is considered one of the most complex mental health disorders. Epigenetics includes all changes in gene expression that do not involve any modifications to DNA sequences. In depression, epigenetic changes may affect the activation or suppression of specific genes involved in mood regulation. Scientists have attempted to determine how specific environmental factors, such as stress or trauma, can trigger epigenetic changes that are closely linked to gene function. By studying these mechanisms, researchers have developed effective treatments and interventions for depression. This discovery not only provides a better understanding of the biological basis of depression, but also suggests new approaches for highly personalized treatments that may be available to individuals suffering from this widespread mental health disorder in the near future. Depression, a significant mental health disorder, is under intense research scrutiny to uncover its molecular foundations. Epigenetics, which focuses on controlling gene expression without altering DNA sequences, offers promising avenues for innovative treatment. This review explores the pivotal role of epigenetics in depression, emphasizing two key aspects: (I) identifying epigenetic targets for new antidepressants and (II) using personalized medicine based on distinct epigenetic profiles, highlighting potential epigenetic focal points such as DNA methylation, histone structure alterations, and non-coding RNA molecules such as miRNAs. Variations in DNA methylation in individuals with depression provide opportunities to target genes that are associated with neuroplasticity and synaptic activity. Aberrant histone acetylation may indicate that antidepressant strategies involve enzyme modifications. Modulating miRNA levels can reshape depression-linked gene expression. The second section discusses personalized medicine based on epigenetic profiles. Analyzing these patterns could identify biomarkers associated with treatment response and susceptibility to depression, facilitating tailored treatments and proactive mental health care. Addressing ethical concerns regarding epigenetic information, such as privacy and stigmatization, is crucial in understanding the biological basis of depression. Therefore, researchers must consider these issues when examining the role of epigenetics in mental health disorders. The importance of epigenetics in depression is a critical aspect of modern medical research. These findings hold great potential for novel antidepressant medications and personalized treatments, which would significantly improve patient outcomes, and transform psychiatry. As research progresses, it is expected to uncover more complex aspects of epigenetic processes associated with depression, enhance our comprehension, and increase the effectiveness of therapies. [ABSTRACT FROM AUTHOR]

Epigenomic and metabolic changes impact retinal health and disease. Metabolite levels influence key epigenomic changes that regulate the retinal transcriptome. Epigenome-metabolism crosstalk underlies retinal adaptation to aging and the environment. The epigenome–metabolism nexus suggests interventions for retinal diseases. Intimate links between epigenome modifications and metabolites allude to a crucial role of cellular metabolism in transcriptional regulation. Retina, being a highly metabolic tissue, adapts by integrating inputs from genetic, epigenetic, and extracellular signals. Precise global epigenomic signatures guide development and homeostasis of the intricate retinal structure and function. Epigenomic and metabolic realignment are hallmarks of aging and highlight a link of the epigenome–metabolism nexus with aging-associated multifactorial traits affecting the retina, including age-related macular degeneration and glaucoma. Here, we focus on emerging principles of epigenomic and metabolic control of retinal gene regulation, with emphasis on their contribution to human disease. In addition, we discuss potential mitigation strategies involving lifestyle changes that target the epigenome-metabolome relationship for maintaining retinal function. [ABSTRACT FROM AUTHOR]

Drought significantly challenges global food security, necessitating a comprehensive understanding of plant molecular responses for effective mitigation strategies. Epigenetic modifications, such as DNA methylation and histone modifications, are key in regulating genes and hormones essential for drought response. While microRNAs (miRNAs) primarily regulate gene expression post-transcriptionally, they can also interact with epigenetic pathways as potential effectors that influence chromatin remodeling. Although the role of miRNAs in epigenetic memory is still being explored, understanding their contribution to drought response requires examining these indirect effects on epigenetic modifications. A key aspect of this exploration is epigenetic memory in drought-adapted plants, offering insights into the transgenerational inheritance of adaptive traits. Understanding the mechanisms that govern the maintenance and erasure of these epigenetic imprints provides nuanced insights into how plants balance stability and flexibility in their epigenomes. A major focus is on the dynamic interaction between hormonal pathways—such as those for abscisic acid (ABA), ethylene, jasmonates, and salicylic acid (SA)—and epigenetic mechanisms. This interplay is crucial for fine-tuning gene expression during drought stress, leading to physiological and morphological adaptations that enhance plant drought resilience. This review also highlights the transformative potential of advanced technologies, such as bisulfite sequencing and CRISPR-Cas9, in providing comprehensive insights into plant responses to water deficit conditions. These technologies pave the way for developing drought-tolerant crops, which is vital for sustainable agriculture. [ABSTRACT FROM AUTHOR]

Cell-free DNA (cfDNA) from the bloodstream has been studied for cancer biomarker discovery, and chromatin-derived epigenetic features have come into the spotlight for their potential to expand clinical applications. Methylation, fragmentation, and nucleosome positioning patterns of cfDNA have previously been shown to reveal epigenomic and inferred transcriptomic information. More recently, histone modifications have emerged as a tool to further identify tumor-specific chromatin variants in plasma. A number of sequencing methods have been developed to analyze these epigenetic markers, offering new insights into tumor biology. Features within cfDNA allow for cancer detection, subtype and tissue of origin classification, and inference of gene expression. These methods provide a window into the complexity of cancer and the dynamic nature of its progression. In this review, we highlight the array of epigenetic features in cfDNA that can be extracted from chromatin- and nucleosome-associated organization and outline potential use cases in cancer management. [ABSTRACT FROM AUTHOR]

Chromatin regulation in eukaryotes plays pivotal roles in controlling the developmental regulatory gene network. This review explores the intricate interplay between chromatin regulators and environmental signals, elucidating their roles in shaping plant development. As sessile organisms, plants have evolved sophisticated mechanisms to perceive and respond to environmental cues, orchestrating developmental programs that ensure adaptability and survival. A central aspect of this dynamic response lies in the modulation of versatile gene regulatory networks, mediated in part by various chromatin regulators. Here, we summarized current understanding of the molecular mechanisms through which chromatin regulators integrate environmental signals, influencing key aspects of plant development. [ABSTRACT FROM AUTHOR]

Various models have been established to culture whole follicles of the Preantral stage; however, the process remains inefficient and is an ongoing challenge formation. It is reported that oocyte-cumulus-granulosa complexes (OCGCs) isolated from Early Antral follicles (EAFs) undergo in vitro growth (IVG) and acquire meiotic competence in some animals. However, IVG for the oocyte-granulosa complexes (OGCs) from Preantral Follicles (PAFs) has not been firmly established. The present study indicated that the use of a modified medium with Ascorbic Acid (50 μM) facilitated granulosa cell proliferation, promoted cumulus cell differentiations, and increased antrum formation for the OGCs isolated from PAFs (0.3–0.4 mm). However, the two-dimensional 96-well plate system (2D) experienced smaller size follicles and could not prolong more than 10 days of IVG. Another method is to use an Agarose matrix 3D system to provide a soft, non-adhesive base that supports the IVG of OGCs isolated from PAFs and promotes cell proliferation, antrum formation, and maintenance for 14 days. OGCs that were grown using this method retained their spherical morphology, which in turn helped to attain healthy granulosa cells and maintain their connection with oocytes, in addition, these oocytes significantly increased diameter and lipid content, indicating developmental competence. Our result indicated that the OGCs from PAFs after IVG undergo a change in chromatin morphology and expression of acetylation of histone H3 at lysine 9 (Ac–H3-K9) and methylation of histone H3 at lysine 4 (Me–H3–K4), similar to the in vivo oocytes isolated from the ovary. Likewise, IVG oocytes cultured for maturation showed full cumulus expansion and reached mature oocytes. Furthermore, after in vitro maturation, IVG oocytes underwent the first cleavage following parthenogenetic activation. In conclusion, while most studies used whole follicles from the Preantral stage for IVG, our research finding was the first to reveal that oocytes isolated from the final stage of PAFs can migrate out of the follicle and undergo IVG under suitable conditions. • Agarose matrix 3D provided a soft, non-adhesive base that supported IVG of Oocyte-Granulosa Complexes isolated from preantral follicles (PAFs). • OGCs grown on agarose-based 3D retained their spherical morphology, promoted cell proliferation, antrum formation, and maintenance for 14 days. • Oocytes grown on agarose-based 3D significantly increased in diameter and lipid content, resulting in improved developmental competence. • We confirm the first report that oocytes isolated from the final stage of PAFs can migrate out of the follicle and undergo IVG-suitable conditions. [ABSTRACT FROM AUTHOR]

Skeletal muscular atrophy is a complex disease involving a large number of gene expression regulatory networks and various biological processes. Despite extensive research on this topic, its underlying mechanisms remain elusive, and effective therapeutic approaches are yet to be established. Recent studies have shown that epigenetics play an important role in regulating skeletal muscle atrophy, influencing the expression of numerous genes associated with this condition through the addition or removal of certain chemical modifications at the molecular level. This review article comprehensively summarizes the different types of modifications to DNA, histones, RNA, and their known regulators. We also discuss how epigenetic modifications change during the process of skeletal muscle atrophy, the molecular mechanisms by which epigenetic regulatory proteins control skeletal muscle atrophy, and assess their translational potential. The role of epigenetics on muscle stem cells is also highlighted. In addition, we propose that alternative splicing interacts with epigenetic mechanisms to regulate skeletal muscle mass, offering a novel perspective that enhances our understanding of epigenetic inheritance's role and the regulatory network governing skeletal muscle atrophy. Collectively, advancements in the understanding of epigenetic mechanisms provide invaluable insights into the study of skeletal muscle atrophy. Moreover, this knowledge paves the way for identifying new avenues for the development of more effective therapeutic strategies and pharmaceutical interventions. [ABSTRACT FROM AUTHOR]

Epigenetic regulation, notably histone post-translational modification (PTM), has emerged as a major transcriptional control of gene expression during cellular stress adaptation. In the present study, we use an acid extraction method to isolate total histone protein and investigate dynamic changes in 23 well-characterized histone methylations/acetylations in the brains of wood frogs subject to 24-h freezing and subsequent 8-h thawed recovery conditions. Our results identify four histone PTMs (H2BK5ac, H3K14ac, H3K4me3, H3K9me2) and three histone proteins (H1.0, H2B, H4) that were significantly (p < 0.05) responsive to freeze-thaw in freeze-tolerant R. sylvatica brains. Two other permissive modifications (H3R8me2a, H3K9ac) also trended downwards following freezing stress. Together, these data are strongly supportive of the proposed global transcriptional states of hypometabolic freeze tolerance and rebounded thawed recovery. Our findings shed light on the intricate interplay between epigenetic regulation, gene transcription and energy metabolism in wood frogs' adaptive response to freezing stress. [ABSTRACT FROM AUTHOR]

Seasonal adaptation in animals is a complex process that involves genetic, epigenetic, and environmental factors. The present review explores recent studies on epigenetic mechanisms implicated in seasonal adaptation in animals. The review is divided into three main sections, each focusing on a different epigenetic mechanism: DNA methylation, histone modifications, and non-coding RNA. Additionally, the review delves into the current understanding of how these epigenetic factors contribute to the regulation of circadian and seasonal cycles. Understanding these molecular mechanisms provides the first step in deciphering the complex interplay between genetics, epigenetics, and the environment in driving seasonal adaptation in animals. By exploring these mechanisms, a better understanding of how animals adapt to changing environmental conditions can be achieved. [ABSTRACT FROM AUTHOR]

Ultraviolet B (UVB) radiation represents a major carcinogen for the development of all skin cancer types. Mechanistically, UVB induces damage to DNA in the form of lesions, including cyclobutane pyrimidine dimers (CPDs). Disruption of the functional repair processes, such as nucleotide excision repair (NER), allows persistence of DNA damage and contributes to skin carcinogenesis. Recent work has implicated m6A RNA methylation and its regulatory proteins as having critical roles in facilitating UVB‐induced DNA damage repair. However, the biological functions of the m6A reader YTHDC2 are unknown in this context. Here, we show that YTHDC2 inhibition enhances the repair of UVB‐induced DNA damage. We discovered that YTHDC2 inhibition increased the expression of PTEN while it decreased the expression of the PRC2 component SUZ12 and the levels of the histone modification H3K27me3. However, none of these functions were causally linked to the improvements in DNA repair, suggesting that the mechanism utilized by YTHDC2 may be unconventional. Moreover, inhibition of the m6A writer METTL14 reversed the effect of YTHDC2 inhibition on DNA repair while inhibition of the m6A eraser FTO mimicked the effect of YTHDC2 inhibition, indicating that YTHDC2 may regulate DNA repair through the m6A pathway. Finally, compared to normal human skin, YTHDC2 expression was upregulated in human cutaneous squamous cell carcinomas (cSCC), suggesting that it may function as a tumor‐promoting factor in skin cancer. Taken together, our findings demonstrate that the m6A reader YTHDC2 plays a role in regulating UVB‐induced DNA damage repair and may serve as a potential biomarker in cSCC. [ABSTRACT FROM AUTHOR]

Understanding the regulatory mechanisms of gene expression is a crucial objective in genomics. Although the DNA sequence near the transcription start site (TSS) offers valuable insights, recent methods suggest that analyzing only the surrounding DNA may not suffice to accurately predict gene expression levels. We developed GENet (Gene Expression Network from Histone and Transcription Factor Integration), a novel approach that integrates essential regulatory signals from transcription factors and histone modifications into a graph-based model. GENet extends beyond simple DNA sequence analysis by incorporating additional layers of genetic control, which are vital for determining gene expression. Our method markedly enhances the prediction of mRNA levels compared to previous models that depend solely on DNA sequence data. The results underscore the significance of including comprehensive regulatory information in gene expression studies. GENet emerges as a promising tool for researchers, with potential applications extending from fundamental biological research to the development of medical therapies. [ABSTRACT FROM AUTHOR]

Epigenetic changes have been established to be a hallmark of aging, which implies that aging science requires collaborating with the field of chromatin biology. DNA methylation patterns, changes in relative abundance of histone post-translational modifications, and chromatin remodeling are the central players in modifying chromatin structure. Aging is commonly associated with an overall increase in chromatin instability, loss of homeostasis, and decondensation. However, numerous publications have highlighted that the link between aging and chromatin changes is not nearly as linear as previously expected. This complex interplay of these epigenetic elements during the lifetime of an organism likely contributes to cellular senescence, genomic instability, and disease susceptibility. Yet, the causal links between these phenomena still need to be fully unraveled. In this perspective article, we discuss potential future directions of aging chromatin biology. [ABSTRACT FROM AUTHOR]

Abstract During the development of multicellular organisms and cell differentiation, the chromatin structure in the cell nucleus undergoes extensive changes, and the nucleosome structure is formed by a combination of various histone variants. Histone variants with diverse posttranslational modifications are known to play crucial roles in different regulatory functions. We have previously reported that H3t, a testis-specific histone variant, is essential for spermatogenesis. To elucidate the function of this chromatin molecule in vivo, we generated knock-in mice with a FLAG tag attached to the carboxyl terminus of H3t. In the present study, we evaluated the utility of the generated knock-in mice and comprehensively analyzed posttranslational modifications of canonical H3 and H3t using mass spectrometry. Herein, we found that H3t-FLAG was incorporated into spermatogonia and meiotic cells in the testes, as evidenced by immunostaining of testicular tissue. According to the mass spectrometry analysis, the overall pattern of H3t-FLAG posttranslational modification was comparable to that of the control H3, while the relative abundances of certain specific modifications differed between H3t-FLAG and the control bulk H3. The generated knock-in mice could be valuable for analyzing the function of histone variants in vivo.

Abstract Skeletal muscular atrophy is a complex disease involving a large number of gene expression regulatory networks and various biological processes. Despite extensive research on this topic, its underlying mechanisms remain elusive, and effective therapeutic approaches are yet to be established. Recent studies have shown that epigenetics play an important role in regulating skeletal muscle atrophy, influencing the expression of numerous genes associated with this condition through the addition or removal of certain chemical modifications at the molecular level. This review article comprehensively summarizes the different types of modifications to DNA, histones, RNA, and their known regulators. We also discuss how epigenetic modifications change during the process of skeletal muscle atrophy, the molecular mechanisms by which epigenetic regulatory proteins control skeletal muscle atrophy, and assess their translational potential. The role of epigenetics on muscle stem cells is also highlighted. In addition, we propose that alternative splicing interacts with epigenetic mechanisms to regulate skeletal muscle mass, offering a novel perspective that enhances our understanding of epigenetic inheritance’s role and the regulatory network governing skeletal muscle atrophy. Collectively, advancements in the understanding of epigenetic mechanisms provide invaluable insights into the study of skeletal muscle atrophy. Moreover, this knowledge paves the way for identifying new avenues for the development of more effective therapeutic strategies and pharmaceutical interventions.

Abstract Background The prevalence of infertility among couples is estimated to range from 8 to 12%. A paradigm shift has occurred in understanding of infertility, challenging the notion that it predominantly affects women. It is now acknowledged that a significant proportion, if not the majority, of infertility cases can be attributed to male-related factors. Various elements contribute to male reproductive impairments, including aberrant sperm production caused by pituitary malfunction, testicular malignancies, aplastic germ cells, varicocele, and environmental factors. Main body The epigenetic profile of mammalian sperm is distinctive and specialized. Various epigenetic factors regulate genes across different levels in sperm, thereby affecting its function. Changes in sperm epigenetics, potentially influenced by factors such as environmental exposures, could contribute to the development of male infertility. Conclusion In conclusion, this review investigates the latest studies pertaining to the mechanisms of epigenetic changes that occur in sperm cells and their association with male reproductive issues.

Abstract The enzymes performing protein post-translational modifications (PTMs) form a critical post-translational regulatory circuitry that orchestrates literally all cellular processes in the organism. In particular, the balance between cellular stemness and differentiation is crucial for the development of multicellular organisms. Importantly, the fine-tuning of this balance on the genetic level is largely mediated by specific PTMs of histones including lysine methylation. Lysine methylation is carried out by special enzymes (lysine methyltransferases) that transfer the methyl group from S-adenosyl-L-methionine to the lysine residues of protein substrates. Set7/9 is one of the exemplary protein methyltransferases that however, has not been fully studied yet. It was originally discovered as histone H3 lysine 4-specific methyltransferase, which later was shown to methylate a number of non-histone proteins that are crucial regulators of stemness and differentiation, including p53, pRb, YAP, DNMT1, SOX2, FOXO3, and others. In this review we summarize the information available to date on the role of Set7/9 in cellular differentiation and tissue development during embryogenesis and in adult organisms. Finally, we highlight and discuss the role of Set7/9 in pathological processes associated with aberrant cellular differentiation and self-renewal, including the formation of cancer stem cells.

Abstract Background Given their physiological similarities to humans, pigs are increasingly used as model organisms in human-oriented biomedical studies. Additionally, their value to animal agriculture across the globe has led to the development of numerous studies to investigate how to improve livestock welfare and production efficiency. As such, pigs are uniquely poised as compelling models that can yield findings with potential implications in both human and animal contexts. Despite this, many gaps remain in our knowledge about the foundational mechanisms that govern gene expression in swine across different developmental stages, particularly in early development. To address some of these gaps, we profiled the histone marks H3K4me3, H3K27ac, and H3K27me3 and the SWI/SNF central ATPase BRG1 in two porcine cell lines representing discrete early developmental time points and used the resulting information to construct predicted chromatin state maps for these cells. We combined this approach with analysis of publicly available RNA-seq data to examine the relationship between epigenetic status and gene expression in these cell types. Results In porcine fetal fibroblast (PFF) and trophectoderm cells (PTr2), we saw expected patterns of enrichment for each of the profiled epigenetic features relative to specific genomic regions. H3K4me3 was primarily enriched at and around global gene promoters, H3K27ac was enriched in promoter and intergenic regions, H3K27me3 had broad stretches of enrichment across the genome and narrower enrichment patterns in and around the promoter regions of some genes, and BRG1 primarily had detectable enrichment at and around promoter regions and in intergenic stretches, with many instances of H3K27ac co-enrichment. We used this information to perform genome-wide chromatin state predictions for 10 different states using ChromHMM. Using the predicted chromatin state maps, we identified a subset of genomic regions marked by broad H3K4me3 enrichment, and annotation of these regions revealed that they were highly associated with essential developmental processes and consisted largely of expressed genes. We then compared the identities of the genes marked by these regions to genes identified as cell-type-specific using transcriptome data and saw that a subset of broad H3K4me3-marked genes was also specifically expressed in either PFF or PTr2 cells. Conclusions These findings enhance our understanding of the epigenetic landscape present in early swine development and provide insight into how variabilities in chromatin state are linked to cell identity. Furthermore, this data captures foundational epigenetic details in two valuable porcine cell lines and contributes to the growing body of knowledge surrounding the epigenetic landscape in this species.

Eko Fuji Ariyanto,1 Ibnu Wijaya,2 Zaky Alif Pradian,2 Agung Putri Mayasari Bhaskara,2 Putri Halleyana Adrikni Rahman,1 Nandina Oktavia1 1Department of Biomedical Sciences, Faculty of Medicine, Universitas Padjadjaran, Sumedang, Indonesia; 2Faculty of Medicine, Universitas Padjadjaran, Sumedang, IndonesiaCorrespondence: Eko Fuji Ariyanto, Department of Biomedical Sciences, Faculty of Medicine, Universitas Padjadjaran, Sumedang, Indonesia, Email fuji@unpad.ac.idAbstract: Atherosclerosis is one of the most dominant pathological processes responsible in cardiovascular diseases (CVD) caused by cholesterol accumulation accompanied by inflammation in the arteries which will subsequently lead to further complications, including myocardial infarction and stroke. Although the incidence of atherosclerosis is decreasing in some countries, it is still considered the leading cause of death worldwide. Atherosclerosis is a vascular pathological process that is chronically inflammatory and is characterized by the invasion of inflammatory cells and cytokines. Many reports have unraveled the pivotal roles of epigenetics such as DNA methylation, post-translational histone modifications, and non-coding RNAs (ncRNAs) in atherogenesis, which regulate the expression of numerous genes related to various responsible pathways. Many studies have been conducted to develop new therapeutical approaches based on epigenetic changes for combating atherosclerosis. This review elaborates on recent updates on the development of new atherosclerosis drugs whose mechanism of action is associated with the modulation of DNA methylation, posttranslational histone modifications, and ncRNA-based gene regulation.Keywords: atherosclerosis, DNA methylation, histone modifications, non-coding RNAs, pharmacotherapy

Parkinson's disease is a progressive neurodegenerative disorder, predominantly of the motor system. Although some genetic components and cellular mechanisms of Parkinson's have been identified, much is still unknown. In recent years, emerging evidence has indicated that non-DNA-sequence variation (in particular epigenetic mechanisms) is likely to play a crucial role in the development and progression of the disease. Here, we present an up-to-date overview of epigenetic processes including DNA methylation, DNA hydroxymethylation, histone modifications and non-coding RNAs implicated in the brain of those with Parkinson's disease. We will also discuss the limitations of current epigenetic research in Parkinson's disease, the advantages of simultaneously studying genetics and epigenetics, and putative novel epigenetic therapies. [ABSTRACT FROM AUTHOR]

This review article critically examines the pivotal role of chromatin organization in gene regulation, cellular differentiation, disease progression and aging. It explores the dynamic between the euchromatin and heterochromatin, coded by a complex array of histone modifications that orchestrate essential cellular processes. We discuss the pathological impacts of chromatin state misregulation, particularly in cancer and accelerated aging conditions such as progeroid syndromes, and highlight the innovative role of epigenetic therapies and artificial intelligence (AI) in comprehending and harnessing the histone code toward personalized medicine. In the context of aging, this review explores the use of AI and advanced machine learning (ML) algorithms to parse vast biological datasets, leading to the development of predictive models for epigenetic modifications and providing a framework for understanding complex regulatory mechanisms, such as those governing cell identity genes. It supports innovative platforms like CEFCIG for high-accuracy predictions and tools like GridGO for tailored ChIP-Seq analysis, which are vital for deciphering the epigenetic landscape. The review also casts a vision on the prospects of AI and ML in oncology, particularly in the personalization of cancer therapy, including early diagnostics and treatment optimization for diseases like head and neck and colorectal cancers by harnessing computational methods, AI advancements and integrated clinical data for a transformative impact on healthcare outcomes. [ABSTRACT FROM AUTHOR]

Metabolism includes anabolism and catabolism, which play an essential role in many biological processes. Chromatin modifications are post‐translational modifications of histones and nucleic acids that play important roles in regulating chromatin‐associated processes such as gene transcription. There is a tight connection between metabolism and chromatin modifications. Many metabolic enzymes and metabolites coordinate cellular activities with alterations in nutrient availability by regulating gene expression through epigenetic mechanisms such as DNA methylation and histone modifications. The dysregulation of gene expression by metabolism and epigenetic modifications may lead to diseases such as diabetes and cancer. Recent studies reveal that metabolic enzymes and metabolites specifically regulate chromatin modifications, including modification types, modification residues and chromatin regions. This specific regulation has been implicated in the development of human diseases, yet the underlying mechanisms are only beginning to be uncovered. In this review, we summarise recent studies of the molecular mechanisms underlying the metabolic regulation of histone and DNA modifications and discuss how they contribute to pathogenesis. We also describe recent developments in technologies used to address the key questions in this field. We hope this will inspire further in‐depth investigations of the specific regulatory mechanisms involved, and most importantly will shed lights on the development of more effective disease therapies. [ABSTRACT FROM AUTHOR]

Background: The prevalence of infertility among couples is estimated to range from 8 to 12%. A paradigm shift has occurred in understanding of infertility, challenging the notion that it predominantly affects women. It is now acknowledged that a significant proportion, if not the majority, of infertility cases can be attributed to male-related factors. Various elements contribute to male reproductive impairments, including aberrant sperm production caused by pituitary malfunction, testicular malignancies, aplastic germ cells, varicocele, and environmental factors. Main body: The epigenetic profile of mammalian sperm is distinctive and specialized. Various epigenetic factors regulate genes across different levels in sperm, thereby affecting its function. Changes in sperm epigenetics, potentially influenced by factors such as environmental exposures, could contribute to the development of male infertility. Conclusion: In conclusion, this review investigates the latest studies pertaining to the mechanisms of epigenetic changes that occur in sperm cells and their association with male reproductive issues. [ABSTRACT FROM AUTHOR]

The development of childhood obesity is a complex process influenced by a combination of genetic predisposition and environmental factors, such as sleep, diet, physical activity, and socioeconomic status. Long-term solutions for decreasing the risk of childhood obesity remain elusive, despite significant advancements in promoting health and well-being in school and at home. Challenges persist in areas such as adherence to interventions, addressing underlying social determinants, and individual differences in response to treatment. Over the last decade, there has been significant progress in epigenetics, along with increased curiosity in gaining insights into how sleep and lifestyle decisions impact an individual's health. Epigenetic modifications affect the expression of genes without causing changes to the fundamental DNA sequence. In recent years, numerous research studies have explored the correlation between sleep and the epigenome, giving a better understanding of DNA methylation, histone modification, and non-coding RNAs. Although significant findings have been made about the influence of sleep on epigenetics, a notable gap exists in the literature concerning sleep-related genes specifically associated with childhood obesity. Consequently, it is crucial to delve deeper into this area to enhance our understanding. Therefore, this review primarily focuses on the connection between sleep patterns and epigenetic modifications in genes related to childhood obesity. Exploring the interplay between sleep, epigenetics, and childhood obesity can potentially contribute to improved overall health outcomes. This comprehensive review encompasses studies focusing on sleep-related genes linked to obesity. [ABSTRACT FROM AUTHOR]

Primary open angle glaucoma (POAG) is defined as a "genetically complex trait", where modifying factors act on a genetic predisposing background. For the majority of glaucomatous conditions, DNA variants are not sufficient to explain pathogenesis. Some genes are clearly underlying the more "Mendelian" forms, while a growing number of related polymorphisms in other genes have been identified in recent years. Environmental, dietary, or biological factors are known to influence the development of the condition, but interactions between these factors and the genetic background are poorly understood. Several studies conducted in recent years have led to evidence that epigenetics, that is, changes in the pattern of gene expression without any changes in the DNA sequence, appear to be the missing link. Different epigenetic mechanisms have been proven to lead to glaucomatous changes in the eye, principally DNA methylation, post-translational histone modification, and RNA-associated gene regulation by non-coding RNAs. The aim of this work is to define the principal epigenetic actors in glaucoma pathogenesis. The identification of such mechanisms could potentially lead to new perspectives on therapeutic strategies. [ABSTRACT FROM AUTHOR]

Chronic kidney disease (CKD) is characterized by persistent kidney dysfunction, ultimately resulting in end-stage renal disease (ESRD). Renal fibrosis is a crucial pathological feature of CKD and ESRD. However, there is no effective treatment for this condition. Despite the complex molecular mechanisms involved in renal fibrosis, increasing evidence highlights the crucial role of histone modification in its regulation. The reversibility of histone modifications offers promising avenues for therapeutic strategies to block or reverse renal fibrosis. Therefore, a comprehensive understanding of the regulatory implications of histone modifications in fibrosis may provide novel insights into more effective and safer therapeutic approaches. This review highlights the regulatory mechanisms and recent advances in histone modifications in renal fibrosis, particularly histone methylation and histone acetylation. The aim is to explore the potential of histone modifications as targets for treating renal fibrosis. [ABSTRACT FROM AUTHOR]

The enzymes performing protein post-translational modifications (PTMs) form a critical post-translational regulatory circuitry that orchestrates literally all cellular processes in the organism. In particular, the balance between cellular stemness and differentiation is crucial for the development of multicellular organisms. Importantly, the fine-tuning of this balance on the genetic level is largely mediated by specific PTMs of histones including lysine methylation. Lysine methylation is carried out by special enzymes (lysine methyltransferases) that transfer the methyl group from S-adenosyl-L-methionine to the lysine residues of protein substrates. Set7/9 is one of the exemplary protein methyltransferases that however, has not been fully studied yet. It was originally discovered as histone H3 lysine 4-specific methyltransferase, which later was shown to methylate a number of non-histone proteins that are crucial regulators of stemness and differentiation, including p53, pRb, YAP, DNMT1, SOX2, FOXO3, and others. In this review we summarize the information available to date on the role of Set7/9 in cellular differentiation and tissue development during embryogenesis and in adult organisms. Finally, we highlight and discuss the role of Set7/9 in pathological processes associated with aberrant cellular differentiation and self-renewal, including the formation of cancer stem cells. [ABSTRACT FROM AUTHOR]

Background: Given their physiological similarities to humans, pigs are increasingly used as model organisms in human-oriented biomedical studies. Additionally, their value to animal agriculture across the globe has led to the development of numerous studies to investigate how to improve livestock welfare and production efficiency. As such, pigs are uniquely poised as compelling models that can yield findings with potential implications in both human and animal contexts. Despite this, many gaps remain in our knowledge about the foundational mechanisms that govern gene expression in swine across different developmental stages, particularly in early development. To address some of these gaps, we profiled the histone marks H3K4me3, H3K27ac, and H3K27me3 and the SWI/SNF central ATPase BRG1 in two porcine cell lines representing discrete early developmental time points and used the resulting information to construct predicted chromatin state maps for these cells. We combined this approach with analysis of publicly available RNA-seq data to examine the relationship between epigenetic status and gene expression in these cell types. Results: In porcine fetal fibroblast (PFF) and trophectoderm cells (PTr2), we saw expected patterns of enrichment for each of the profiled epigenetic features relative to specific genomic regions. H3K4me3 was primarily enriched at and around global gene promoters, H3K27ac was enriched in promoter and intergenic regions, H3K27me3 had broad stretches of enrichment across the genome and narrower enrichment patterns in and around the promoter regions of some genes, and BRG1 primarily had detectable enrichment at and around promoter regions and in intergenic stretches, with many instances of H3K27ac co-enrichment. We used this information to perform genome-wide chromatin state predictions for 10 different states using ChromHMM. Using the predicted chromatin state maps, we identified a subset of genomic regions marked by broad H3K4me3 enrichment, and annotation of these regions revealed that they were highly associated with essential developmental processes and consisted largely of expressed genes. We then compared the identities of the genes marked by these regions to genes identified as cell-type-specific using transcriptome data and saw that a subset of broad H3K4me3-marked genes was also specifically expressed in either PFF or PTr2 cells. Conclusions: These findings enhance our understanding of the epigenetic landscape present in early swine development and provide insight into how variabilities in chromatin state are linked to cell identity. Furthermore, this data captures foundational epigenetic details in two valuable porcine cell lines and contributes to the growing body of knowledge surrounding the epigenetic landscape in this species. [ABSTRACT FROM AUTHOR]

Type 1 diabetes (T1D) affects gastrointestinal (GI) motility, favoring gastroparesis, constipation, and fecal incontinence, which are more prevalent in women. The mechanisms are unknown. Given the G-protein-coupled estrogen receptor's (GPER) role in GI motility, we investigated sex-related diabetes-induced epigenetic changes in GPER. We assessed GPER mRNA and protein expression levels using qPCR and Western blot analyses, and quantified the changes in nuclear DNA methyltransferases and histone modifications (H3K4me3, H3Ac, and H3K27Ac) by ELISA kits. Targeted bisulfite and chromatin immunoprecipitation assays were used to evaluate DNA methylation and histone modifications around the GPER promoter by chromatin immunoprecipitation assays in gastric and colonic smooth muscle tissues of male and female control (CTR) and non-obese diabetic (NOD) mice. GPER expression was downregulated in NOD, with sex-dependent variations. In the gastric smooth muscle, not in colonic smooth muscle, downregulation coincided with differences in methylation ratios between regions 1 and 2 of the GPER promoter of NOD. DNA methylation was higher in NOD male colonic smooth muscle than in NOD females. H3K4me3 and H3ac enrichment decreased in NOD gastric smooth muscle. H3K4me3 levels diminished in the colonic smooth muscle of NOD. H3K27ac levels were unaffected, but enrichment decreased in NOD male gastric smooth muscle; however, it increased in the NOD male colonic smooth muscle and decreased in the female NOD colonic smooth muscle. Male NOD colonic smooth muscle exhibited decreased H3K27ac levels, not female, whereas female NOD colonic smooth muscle demonstrated diminished enrichment of H3ac at the GPER promoter, contrary to male NOD. Sex-specific epigenetic mechanisms contribute to T1D-mediated suppression of GPER expression in the GI tract. These insights advance our understanding of T1D complications and suggest promising avenues for targeted therapeutic interventions. [ABSTRACT FROM AUTHOR]

Congenital heart disease (CHD) refers to congenital structural abnormalities of the heart, including defects in the myocardial wall, valves, and major blood vessels. While genetic factors such as mutations and aberrant gene expression during embryogenesis contribute to CHD, they only account for part of cases. There are more and more studies on epigenetic histone modifications in CHD, suggesting that they are increasingly important in the pathogenesis of CHD. With the development of mass spectrometry-based proteomics technology, a spectrum of novel histone post-translational modifications, such as succinylation, glycosylation, lactylation, and β-hydroxybutyrylation, have been uncovered to contribute to various diseases. However, it remains unclear how these novel modifications regulate gene expression and pathological processes during the development and progression of CHD. This article will delve into the mechanisms of various histone modifications that regulate genes associated with cardiac development. It will approach the topic from both the perspective of classic histone modifications and novel histone modifications, aiming to unveil the significance of histone-driven epigenetic mechanisms in the etiology of CHD. Furthermore, it seeks to offer insights into the etiology of CHD, providing a theoretical basis for clinical treatment and timely prevention of this condition. [ABSTRACT FROM AUTHOR]

The possibility of using epigenetics in forensic investigation has gradually risen over the last few years. Epigenetic changes with their dynamic nature can either be inherited or accumulated throughout a lifetime and be reversible, prompting investigation of their use across various fields. In forensic sciences, multiple applications have been proposed, such as the discrimination of monozygotic twins, identifying the source of a biological trace left at a crime scene, age prediction, determination of body fluids and tissues, human behavior association, wound healing progression, and determination of the post-mortem interval (PMI). Despite all these applications, not all the studies considered the impact of PMI and post-sampling effects on the epigenetic modifications and the tissue-specificity of the epigenetic marks. This review aims to highlight the substantial forensic significance that epigenetics could support in various forensic investigations. First, basic concepts in epigenetics, describing the main epigenetic modifications and their functions, in particular, DNA methylation, histone modifications, and non-coding RNA, with a particular focus on forensic applications, were covered. For each epigenetic marker, post-mortem stability and tissue-specificity, factors that should be carefully considered in the study of epigenetic biomarkers in the forensic context, have been discussed. The advantages and limitations of using post-mortem tissues have been also addressed, proposing directions for these innovative strategies to analyze forensic specimens. [ABSTRACT FROM AUTHOR]

Renal fibrosis is a pathogenic intermediate stage of chronic kidney disease (CKD). Nephrotoxicants including arsenic can cause kidney fibrosis through induction of oxidative stress and epigenetic aberrations. Epigallocatechin‐3‐gallate (EGCG), a green tea polyphenol, is known to have antioxidant and epigenetic modulation properties. Whether EGCG, through its antioxidant and epigenetic modulating activities, can attenuate fibrogenesis is not known. Therefore, the objective of this study was to determine whether EGCG can attenuate arsenic‐induced acute injury and long‐term exposure associated fibrogenicity in kidney epithelial cells. To address this question, two human kidney epithelial cell lines Caki‐1 and HK‐2 exposed to arsenic for both acute and long‐term durations were treated with EGCG. The protective effect of EGCG on arsenic‐induced cytotoxicity and fibrogenicity were evaluated by measuring the cell growth, reactive oxygen species (ROS) production, genes expression, and epigenetic changes in histone marks. Results revealed that EGCG has a protective effect in arsenic‐induced acute cytotoxicity in these cells. EGCG scavenges the increased levels of ROS in arsenic exposed cells. Aberrant expression of fibrogenic genes in arsenic exposed cells were restored by EGCG. Abrogation of arsenic‐induced fibrogenic changes was also associated with EGCG‐mediated restoration of arsenic‐induced aberrant expression of epigenetic regulatory proteins and histone marks. Novel findings of this study suggest that EGCG, through its antioxidant and epigenetic modulation capacities, has protective effects against arsenic‐induced cytotoxicity and fibrogenic changes in kidney epithelial cells. [ABSTRACT FROM AUTHOR]

SUMMARY: Controlled transcription of genes is critical for cell differentiation and development. Gene expression regulation therefore involves a multilayered control from nucleosome composition in histone variants and their post‐translational modifications to higher‐order folding of chromatin fibers and chromatin interactions in nuclear space. Recent technological advances have allowed gaining insight into these mechanisms, the interplay between local and higher‐order chromatin organization, and the dynamic changes that occur during stress response and developmental transitions. In this review, we will discuss chromatin organization from the nucleosome to its three‐dimensional structure in the nucleus, and consider how these different layers of organization are maintained during the cell cycle or rapidly reprogrammed during development. Significance Statement: Chromatin organization contributes to gene expression control. In this review, we examine the interplay between local and higher‐order chromatin organization and the dynamic changes that occur during stress response and developmental transitions. [ABSTRACT FROM AUTHOR]

T‐cell acute lymphoblastic leukemia (T‐ALL) is an aggressive malignancy accounting for 10%–15% of pediatric and 20%–25% of adult ALL cases. Epigenetic irregularities in T‐ALL include alterations in both DNA methylation and the post‐translational modifications on histones which together play a critical role in the initiation and development of T‐ALL. Characterizing the oncogenic mutations that result in these epigenetic changes combined with the reversibility of epigenetic modifications represents an opportunity for the development of epigenetic therapies. Oncogenic mutations and deregulated expression of DNA methyltransferases (DNMTs), Ten‐Eleven Translocation dioxygenases (TETs), Histone acetyltransferases (HATs) and members of Polycomb Repressor Complex 2 (PRC2) have all been identified in T‐ALL. This review focuses on the current understanding of how these mutations lead to epigenetic changes in T‐ALL, their association with disease pathogenesis and the current efforts to exploit these clinically through the development of epigenetic therapies in T‐ALL treatment. [ABSTRACT FROM AUTHOR]