Epigenetics & Chromatin最新文献

Background: Epigenetic modifications provide mechanisms for influencing gene expression, regulating cell differentiation and maintaining long-term memory of cellular identity and function. As oocytes transmit epigenetic information to offspring, correct establishment of the oocyte epigenome is important for normal offspring development. Oocyte epigenetic programming is highly complex, involving a range of epigenetic modifiers which interact to establish a specific distribution of DNA methylation and histone modifications. Disruptions to oocyte epigenetic programming can alter epigenetic memory and prevent normal developmental outcomes in the next generation. Therefore, it is critical that we further our understanding of the interdependent relationships between various epigenetic modifiers and modifications during oogenesis.

Results: In this study we investigated the spatial and temporal distribution of a range of epigenetic modifiers and modifications in growing oocytes of primordial to antral follicles. We provide comprehensive immunofluorescent profiles of SETD2, H3K36me3, KDM6A, RBBP7, H3K27me3, DNMT3A and DNMT3L and compare these profiles to our previously published profiles of the Polycomb Repressive Complex 2 components EED, EZH2 and SUZ12 in growing oocytes of wildtype mice. In addition, we examined the nuclear levels and spatial distribution of these epigenetic modifiers and modifications in oocytes that lacked the essential Polycomb Repressive Complex 2 subunit, EED. Notably, histone remodelling in primary-secondary follicle oocytes preceded upregulation of DNMT3A and DNMT3L in secondary-antral follicle oocytes. Moreover, loss of EED and H3K27me3 led to significantly increased levels of the H3K36me3 methyltransferase SETD2 during early-mid oocyte growth, although the average levels of H3K36me3 were unchanged.

Conclusions: Overall, these data demonstrate that oocyte epigenetic programming is a highly ordered process, with histone remodelling in early growing oocytes preceding de novo DNA methylation in secondary-antral follicle oocytes. These results indicate that tight temporal and spatial regulation of histone modifiers and modifications is essential to ensure correct establishment of the unique epigenome present in fully grown oocytes. Further understanding of the temporal and spatial relationships between different epigenetic modifications and how they interact is essential for understanding how germline epigenetic programming affects inheritance and offspring development in mammals, including humans.

TIP60 is a crucial lysine acetyltransferase protein that catalyzes the acetylation of histone and non-histone proteins. This enzyme plays a crucial role in maintaining genomic integrity, by participating in DNA damage repair, ensuring accurate chromosomal segregation, and regulating a myriad of cellular processes such as apoptosis, autophagy, and wound-induced cell migration. One of the primary mechanisms through which TIP60 executes these diverse cellular functions is via post-translational modifications (PTMs). Over the years, extensive studies have demonstrated the importance of PTMs in controlling protein functions. This review aims to summarize the findings on PTMs occurring on the TIP60 protein and their functional implications. We also discuss previously uncharacterized PTM sites identified on TIP60 and examine their relationship with cancer-associated mutations, with a particular focus on residues potentially modified by various PTMs, to understand the cause of deregulation of TIP60 in various cancers.

Background: DNA methylation plays a crucial role in gene regulation and epigenetic inheritance across diverse organisms. Daphnia magna, a model organism in ecological and evolutionary research, has been widely used to study environmental responses, pharmaceutical toxicity, and developmental plasticity. However, its DNA methylation landscape and age-related epigenetic changes remain incompletely understood.

Results: In this study, we characterized DNA methyltransferases (DNMTs) and mapped DNA methylation across the D. magna genome using whole-genome bisulfite sequencing. Our analysis identified three DNMTs: a highly expressed but nonfunctional de novo methyltransferase (DNMT3.1), alongside lowly expressed yet functional de novo methyltransferase (DNMT3.2) and maintenance methyltransferase (DNMT1). D. magna exhibits overall low DNA methylation, targeting primarily CpG dinucleotides. Methylation is sparse at promoters but elevated in the first exons downstream of transcription start sites, with these exons showing hypermethylation relative to adjacent introns. To examine age-associated DNA methylation changes, we analyzed D. magna individuals across multiple life stages. Our results showed no significant global differences in DNA methylation levels between young, mature, and old individuals, nor any age-related clustering in dimensionality reduction analyses. Attempts to construct an epigenetic clock using machine learning models did not yield accurate age predictions, likely due to the overall low DNA methylation levels and lack of robust age-associated methylation changes.

Conclusions: This study provides a comprehensive characterization of D. magna's DNA methylation landscape and DNMT enzymes, highlighting a distinct pattern of exon-biased CpG methylation. Contrary to prior studies, we found no strong evidence supporting age-associated epigenetic changes, suggesting that DNA methylation may have a limited role in aging in D. magna. These findings enhance our understanding of invertebrate epigenetics and emphasize the need for further research into the interplay between DNA methylation, environmental factors, and gene regulation in D. magna.

Macrophage polarization is a dynamic process driven by a complex interplay of cytokine signaling, metabolism, and epigenetic modifications mediated by pathogens. Upon encountering specific environmental cues, monocytes differentiate into macrophages, adopting either a pro-inflammatory (M1) or anti-inflammatory (M2) phenotype, depending on the cytokines present. M1 macrophages are induced by interferon-gamma (IFN-γ) and are characterized by their reliance on glycolysis and their role in host defense. In contrast, M2 macrophages, stimulated by interleukin-4 (IL-4) and interleukin-13 (IL-13), favor oxidative phosphorylation and participate in tissue repair and anti-inflammatory responses. Metabolism is tightly linked to epigenetic regulation, because key metabolic intermediates such as acetyl-coenzyme A (CoA), α-ketoglutarate (α-KG), S-adenosylmethionine (SAM), and nicotinamide adenine dinucleotide (NAD⁺) serve as cofactors for chromatin-modifying enzymes, which in turn, directly influences histone acetylation, methylation, RNA/DNA methylation, and protein arginine methylation. These epigenetic modifications control gene expression by regulating chromatin accessibility, thereby modulating macrophage function and polarization. Histone acetylation generally promotes a more open chromatin structure conducive to gene activation, while histone methylation can either activate or repress gene expression depending on the specific residue and its methylation state. Crosstalk between histone modifications, such as acetylation and methylation, further fine-tunes macrophage phenotypes by regulating transcriptional networks in response to metabolic cues. While arginine methylation primarily functions in epigenetics by regulating gene expression through protein modifications, the degradation of methylated proteins releases arginine derivatives like asymmetric dimethylarginine (ADMA), which contribute directly to arginine metabolism-a key factor in macrophage polarization. This review explores the intricate relationships between metabolism and epigenetic regulation during macrophage polarization. A better understanding of this crosstalk will likely generate novel therapeutic insights for manipulating macrophage phenotypes during infections like tuberculosis and inflammatory diseases such as diabetes.

Background: De novo DNA methylation by DNMT3A is a fundamental epigenetic modification for transcriptional regulation. Histone tails and regulatory proteins regulate DNMT3A, and the crosstalk between these epigenetic mechanisms ensures appropriate DNA methylation patterning. Based on findings showing that Fos ecRNA inhibits DNMT3A activity in neurons, we sought to characterize the contribution of this regulatory RNA in the modulation of DNMT3A in the presence of regulatory proteins and histone tails.

Results: We show that Fos ecRNA and mRNA strongly correlate in primary cortical neurons on a single cell level and provide evidence that Fos ecRNA modulation of DNMT3A at these actively transcribed sites occurs in a sequence-independent manner. Further characterization of the Fos ecRNA-DNMT3A interaction showed that Fos-1 ecRNA binds the DNMT3A tetramer interface and clinically relevant DNMT3A substitutions that disrupt the inhibition of DNMT3A activity by Fos-1 ecRNA are restored by the formation of heterotetramers with DNMT3L. Lastly, using DNMT3L and Fos ecRNA in the presence of synthetic histone H3 tails or reconstituted polynucleosomes, we found that regulatory RNAs play dominant roles in the modulation of DNMT3A activity.

Conclusion: Our results are consistent with a model for RNA regulation of DNMT3A that involves localized production of short RNAs binding to a nonspecific site on the protein, rather than formation of localized RNA/DNA structures. We propose that regulatory RNAs play a dominant role in the regulation of DNMT3A catalytic activity at sites with increased production of regulatory RNAs.

Background: Linker histones constitute a class of proteins that are responsible for the formation of higher-order chromatin structures. Core histones are integral components of nucleosome core particles (NCPs), whereas linker histones bind to linker DNA between NCPs. Heterochromatin protein 1 binding protein 3 (HP1BP3) displays sequence similarity to linker histones, with the exception of the presence of three globular domains in its central region. However, the function of HP1BP3 as a linker histone has not been analyzed previously. The present study aimed to elucidate the function of full-length HP1BP3 as a linker histone variant.

Results: The results of biochemical analyses demonstrate that HP1BP3 efficiently binds to NCPs with similar efficiency as linker histones, thereby forming a chromatosome. Notwithstanding the presence of three globular domains, the results suggest that a single HP1BP3 binds to a single NCP under our biochemical assay condition. Moreover, our findings revealed that the NCP binding activity of HP1BP3 is regulated by linker histone chaperones, nucleophosmin (NPM1) and template activating factor-I (TAF-I). The globular domains and the C-terminal disordered region of HP1BP3 are responsible for binding to histone chaperones. Chromatin immunoprecipitation-sequence analyses demonstrated that HP1BP3 exhibited weak preferences for the genomic loci where histone H3 active modification marks were enriched, whereas a linker histone variant, H1.2, showed weak preferences for the genomic loci where histone H3 inactive modification marks were enriched. It is noteworthy that the preferential binding tendencies of HP1BP3 and H1.2 to active and inactive genomic loci, respectively, are diminished upon the knockdown of either NPM1 or TAF-I.

Conclusions: Our findings indicate that HP1BP3 functions as a linker histone variant and that the chromatin binding preference of linker histones, including HP1BP3, is regulated by linker histone chaperones.

Lysine crotonylation (Kcr), a previously unknown post-translational modification (PTM), plays crucial roles in regulating cellular processes, including gene expression, chromatin remodeling, and cellular metabolism. Kcr is associated with various diseases, including neurodegenerative disorders, cancer, cardiovascular conditions, and metabolic syndromes. Despite advances in identifying crotonylation sites and their regulatory enzymes, the molecular mechanisms by which Kcr influences disease progression remain poorly understood. Understanding the interplay between Kcr and other acylation modifications may reveal opportunities for developing targeted therapies. This review synthesizes current research on Kcr, focusing on its regulatory mechanisms and disease associations, and highlights insights into future exploration in epigenetics and therapeutic interventions.

The origins of many diseases can be traced to the dynamic interplay of genetic predispositions and environmental exposures post-birth. Epigenetic modifications have recently gained prominence as a significant mediator between genetic information and environmental factors, influencing the occurrence and progression of disease. There is a burgeoning body of evidence supports that physical exercise, acting as an external environmental stimulus, exerts a discernible impact on major epigenetic modifications, including histone modifications, DNA methylation, RNA methylation, and non-coding RNA. This effect assumes a pivotal role in the pathogenesis of various human diseases. Exploring the epigenetic molecular mechanisms through which physical exercise enhances human health holds the promise of deepening our understanding of how it improves physiological functions, mitigates disease risks, and establishes a theoretical foundation for employing physical exercise as a non-pharmacological intervention in disease prevention and treatment.

Background: Pulmonary fibrosis is a relentless and ultimately fatal lung disorder. Despite a wealth of research, the intricate molecular pathways that contribute to the onset of PF, especially the aspects related to epigenetic modifications and chromatin dynamics, continue to be elusive and not fully understood.

Methods: Utilizing a bleomycin-induced pulmonary fibrosis model, we conducted a comprehensive analysis of the interplay between chromatin structure, chromatin accessibility, gene expression patterns, and cellular heterogeneity. Our chromatin structure analysis included 5 samples (2 control and 3 bleomycin-treated), while accessibility and expression analysis included 6 samples each (3 control and 3 bleomycin-treated).

Results: We found that chromatin architecture, with its alterations in compartmentalization and accessibility, is positively correlated with genome-wide gene expression changes during fibrosis. The importance of immune system inflammation and extracellular matrix reorganization in fibrosis is underscored by these chromatin alterations. Transcription factors such as PU.1, AP-1, and IRF proteins, which are pivotal in immune regulation, are associated with an increased abundance of their motifs in accessible genomic regions and are correlated with highly expressed genes.

Conclusions: We identified 14 genes that demonstrated consistent changes in their expression, accessibility, and compartmentalization, suggesting their potential as promising targets for the development of treatments for lung fibrosis.