Epigenetics & Chromatin最新文献

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.

DNA methylation, catalyzed by DNA methyltransferases (DNMT), plays pivotal role in regulating embryonic development, gene expression, adaption to environmental stress, and maintaining genome integrity. DNMT family consists of DNMT1, DNMT3A, DNMT3B, and the enzymatically inactive DNMT3L. DNMT3A and DNMT3B establish novel methylation patterns maintained by DNMT1 during replication. Genetic variants of DNMT3A and DNMT3B cause rare diseases such as Tatton-Brown-Rahman and ICF syndromes. Additionally, somatic mutations cause common conditions such as osteoarthritis, osteoporosis, clonal hematopoiesis of indeterminate potential (CHIP), hematologic malignancies, and cancer. While DNMTs have been extensively studied in vitro, in early development and in disease, their detailed physiologic roles remain less understood as in vivo investigations are hindered by the embryonic or perinatal lethality of the knockout mice. To circumvent this problem, tissue-specific Dnmt3a and Dnmt3b knockouts were engineered. This review explores their diverse molecular roles across various organs and cell types and characterizes the phenotype of the knockout mice. We provide a comprehensive collection of over forty tissue-specific knockout models generated by cre recombinase. We highlight the distinct functions of DNMT3A and DNMT3B in germ cells, early development, uterus, hematopoietic differentiation, musculoskeletal development, visceral organs, and nervous system. Our findings indicate that DNMT3A primarily regulates hematopoietic differentiation, while DNMT3B is crucial for cartilage homeostasis and ossification. We emphasize the context-dependent roles of DNMT3A and DNMT3B and demonstrate that they also complement DNMT1 maintenance methyltransferase activity. Overall, the expression patterns of DNMTs across tissues provide insights into potential therapeutic applications for treating neurologic diseases, cancer, and osteoporosis.

Background: DNA methylation plays a crucial role in mammalian development. While methylome changes acquired in the parental genomes are believed to be erased by epigenetic reprogramming, accumulating evidence suggests that methylome changes in sperm caused by environmental factors are involved in the disease phenotypes of the offspring. These findings imply that acquired sperm methylome changes are transferred to the embryo after epigenetic reprogramming. However, our understanding of this process remains incomplete. Our previous study showed that arsenic exposure of F0 pregnant mice paternally increased tumor incidence in F2 offspring. The sperm methylome of arsenic-exposed F1 males exhibited characteristic features, including enrichment of hypomethylated cytosines at the promoters of retrotransposons LINEs and LTRs. Hypomethylation of retrotransposons is potentially detrimental. Determining whether these hypomethylation changes in sperm are transferred to the embryo is important in confirming the molecular pathway of intergenerational transmission of paternal effects of arsenic exposure.

Results: We investigated the methylome of F2 male embryos after epigenetic reprogramming by reduced representation bisulfite sequencing (RRBS) and allele-specific analysis. To do so, embryos were obtained by crossing control or gestationally arsenic-exposed F1 males (C3H/HeN strain) with control females (C57BL/6 strain). The results revealed that the methylome of F2 embryos in the arsenic group was globally hypomethylated and enriched for hypomethylated cytosines in certain genomic regions, including LTR and LINE, as observed in F1 sperm of the arsenic group. Unexpectedly, the characteristic methylome features were detected not only in the paternal genome but also in the maternal genome of embryos. Furthermore, these methylation changes were found to rarely occur at the same positions between F1 sperm and F2 embryos.

Conclusions: The results of this study revealed that the characteristics of arsenic-induced methylome changes in F1 sperm are reproduced in both the paternal and maternal genomes of post-epigenetic reprogramming embryos. Furthermore, the results suggest that this re-establishment is achieved in collaboration with other factors that mediate region-specific methylation changes. These results also highlight the possibility that arsenic-induced sperm methylome changes could contribute to the development of disease predisposition in offspring.

Background: Colorectal cancer (CRC) remains one of the most common causes of cancer-related mortality worldwide. Its progression is influenced by complex interactions involving genetic, epigenetic, and environmental factors. Non-coding RNAs (ncRNAs), including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), have been identified as key regulators of gene expression, affecting diverse biological processes, notably programmed cell death (PCD).

Objective: This review aims to explore the relationship between ncRNAs and PCD in CRC, focusing on how ncRNAs influence cancer cell survival, proliferation, and treatment resistance.

Methods: A comprehensive literature analysis was conducted to examine recent findings on the role of ncRNAs in modulating various PCD mechanisms, including apoptosis, autophagy, necroptosis, and pyroptosis, and their impact on CRC development and therapeutic response.

Results: ncRNAs were found to significantly regulate PCD pathways, impacting tumor growth, metastasis, and treatment sensitivity in CRC. Their influence on these pathways highlights the potential of ncRNAs as biomarkers for early CRC detection and as targets for innovative therapeutic interventions.

Conclusion: Understanding the involvement of ncRNAs in PCD regulation offers new insights into CRC biology. The targeted modulation of ncRNA-PCD interactions presents promising avenues for personalized cancer treatment, which may improve patient outcomes by enhancing therapeutic effectiveness and reducing resistance.

Post-translational modifications of histone H3 on lysine 9, specifically acetylation (H3K9ac) and tri-methylation (H3K9me3), play a critical role in regulating chromatin accessibility. However, the role of these modifications in lineage segregation in the mammalian blastocyst remains poorly understood. We demonstrate that di- and tri-methylation marks, H3K9me2 and H3K9me3, decrease during cavitation and expansion of the rabbit blastocyst. Notably, H3K9me3 levels are particularly low in inner cell mass cells at the onset of blastocyst formation but increase again just before gastrulation. Conversely, H3K9ac is abundant in early blastocyst stages but decreases during the transition from the inner cell mass to the epiblast. These distinct distribution patterns correlate with high expression levels of methyltransferases (EHMT1, EHMT2, SETDB1) and deacetylases (HDAC1, HDAC2, HDAC5) in expanding blastocysts. Functionally, inhibiting H3K9me2/3 through an EHMT1/2 inhibitor disrupts primitive endoderm segregation, whereas enhancing histone acetylation (including H3K9ac) using a class I HDAC inhibitor promotes epiblast expansion at the expense of the primitive endoderm. These modifications impact the expression of genes associated with pluripotency and lineage determination, underscoring the importance of H3K9 modifications in embryonic cell fate decisions.