Epigenetics & Chromatin最新文献

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.

Human immunodeficiency virus type 1 (HIV-1) is a retrovirus that infects multiple immune cell types and integrates into host cell DNA termed provirus. Under antiretroviral control, provirus in cells is able to evade targeting by both host immune surveillance and antiretroviral drug regimens. Additionally, the provirus remains integrated for the life of the cell, and clonal expansion establishes a persistent reservoir. As host cells become quiescent following the acute stage of infection, the provirus also enters a latent state characterized by low levels of transcription and virion production. Proviral latency may last years or even decades, but stimuli such as immune activation, accumulation of viral proteins, and certain medications can trigger reactivation of proviral gene expression. Left untreated, this can lead to virema, development of pathogenic out comes, and even death as the immune system becomes weakened and dysregulated. Over the last few decades, the role of chromatin in both HIV-1 latency and reactivation has been characterized in-depth, and a number of host factors have been identified as key players in modifying the local (2D) chromatin environment of the provirus. Here, the impact of the 2D chromatin environment and its related factors are reviewed. Enzymes that catalyze the addition or removal of covalent groups from histone proteins, such as histone deacetylase complexes (HDACs) and methyltransferases (HMTs) are of particular interest, as they both alter the affinity of histones for proviral DNA and function to recruit other proteins that contribute to chromatin remodeling and gene expression from the provirus. More recently, advances in next-generation sequencing and imaging technology has enabled the study of how the higher-order (3D) chromatin environment relates to proviral latency, including the impacts of integration site and cell type. All together, these multi-dimensional factors regulate latency by influencing the degree of accessibility to the proviral DNA by transcription machinery. Finally, additional implications for therapeutics and functional studies are proposed and discussed.

Background: Epigenes are defined as proteins that perform post-translational modification of histones or DNA, reading of post-translational modifications, form complexes with epigenetic factors or changing the general structure of chromatin. This specialized group of proteins is responsible for controlling the organization of genomic DNA in a cell-type specific fashion, controlling normal development in a spatial and temporal fashion. Moreover, mutations in epigenes have been implicated as causal in germline pediatric disorders and as driver mutations in cancer. Despite their importance to human disease, to date, there has not been a systematic analysis of the sources of functional diversity for epigenes at large. Epigenes' unique functions that require the assembly of pools within the nucleus suggest that their structure and amino acid composition would have been enriched for features that enable efficient assembly of chromatin and DNA for transcription, splicing, and post-translational modifications.

Results: In this study, we assess the functional diversity stemming from gene structure, isoforms, protein domains, and multiprotein complex formation that drive the functions of established epigenes. We found that there are specific structural features that enable epigenes to perform their variable roles depending on the cellular and environmental context. First, epigenes are significantly larger and have more exons compared with non-epigenes which contributes to increased isoform diversity. Second epigenes participate in more multimeric complexes than non-epigenes. Thirdly, given their proposed importance in membraneless organelles, we show epigenes are enriched for substantially larger intrinsically disordered regions (IDRs). Additionally, we assessed the specificity of their expression profiles and showed epigenes are more ubiquitously expressed consistent with their enrichment in pediatric syndromes with intellectual disability, multiorgan dysfunction, and developmental delay. Finally, in the L1000 dataset, we identify drugs that can potentially be used to modulate expression of these genes.

Conclusions: Here we identify significant differences in isoform usage, disordered domain content, and variable binding partners between human epigenes and non-epigenes using various functional genomics datasets from Ensembl, ENCODE, GTEx, HPO, LINCS L1000, and BrainSpan. Our results contribute new knowledge to the growing field focused on developing targeted therapies for diseases caused by epigene mutations, such as chromatinopathies and cancers.

Background: The DNA methylation-based epigenetic clocks are increasingly recognized for their precision in predicting aging and its health implications. Although prior research has identified connections between accelerated epigenetic aging and multiple sclerosis, the chronological and causative aspects of these relationships are yet to be elucidated. Our research seeks to clarify these potential causal links through a bidirectional Mendelian randomization study.

Methods: This analysis employed statistics approaches from genome-wide association studies related to various epigenetic clocks (GrimAge, HannumAge, PhenoAge, and HorvathAge) and multiple sclerosis, utilizing robust instrumental variables from the Edinburgh DataShare (n = 34,710) and the International Multiple Sclerosis Genetics Consortium (including 24,091 controls and 14,498 cases). We applied the inverse-variance weighted approach as our main method for Mendelian randomization, with additional sensitivity analyses to explore underlying heterogeneity and pleiotropy.

Results: Using summary-based Mendelian randomization, we found that HannumAge was associated with multiple sclerosis (OR = 1.071, 95%CI:1.006-1.140, p = 0.033, by inverse-variance weighted). The results suggest that an increase in epigenetic age acceleration of HannumAge promotes the risk of multiple sclerosis. In reverse Mendelian randomization analysis, no evidence of a clear causal association of multiple sclerosis on epigenetic age acceleration was identified.

Conclusions: Our Mendelian randomization analysis revealed that epigenetic age acceleration of HannumAge was causally associated with multiple sclerosis, and provided novel insights for further mechanistic and clinical studies of epigenetic age acceleration-mediated multiple sclerosis.

Background: Histone modification H3K27me3 plays a critical role in normal development and is associated with various diseases, including cancer. This modification forms large chromatin domains, known as Large Organized Chromatin Lysine Domains (LOCKs), which span several hundred kilobases.

Result: In this study, we identify and categorize H3K27me3 LOCKs in 109 normal human samples, distinguishing between long and short LOCKs. Our findings reveal that long LOCKs are predominantly associated with developmental processes, while short LOCKs are enriched in poised promoters and are most associated with low gene expression. Further analysis of LOCKs in different DNA methylation contexts shows that long LOCKs are primarily located in partially methylated domains (PMDs), particularly in short-PMDs, where they are most likely responsible for the low expressions of oncogenes. We observe that in cancer cell lines, including those from esophageal and breast cancer, long LOCKs shift from short-PMDs to intermediate-PMDs and long-PMDs. Notably, a significant subset of tumor-associated long LOCKs in intermediate- and long-PMDs exhibit reduced H3K9me3 levels, suggesting that H3K27me3 compensates for the loss of H3K9me3 in tumors. Additionally, we find that genes upregulated in tumors following the loss of short LOCKs are typically poised promoter genes in normal cells, and their transcription is regulated by the ETS1 transcription factor.

Conclusion: These results provide new insights into the role of H3K27me3 LOCKs in cancer and underscore their potential impact on epigenetic regulation and disease mechanisms.