Epigenetics & Chromatin最新文献

Background: Obsessive Compulsive Disorder (OCD) affects 2 to 3% of the population and is marked by intrusive thoughts and repetitive behaviours. OCD is increasingly recognized as a polygenic disorder involving gene-environment interactions, with genetic risk largely driven by common variants and a smaller contribution from rare pathogenic variation. Despite these insights, the functional roles of implicated genes remain unclear. Recent genomic studies suggest that chromatin dysregulation contributes to the pathogenesis of OCD.

Results: We analysed the recently published large-scale genome-wide association study meta-analysis of OCD by Strom et al., which included 53,660 cases and over 2 million controls. This study identified 30 genome-wide significant loci and approximately 11,500 common variants, together explaining 90% of OCD heritability. We analysed the 251 prioritized genes mapped through six genomic methods identified in this study. Gene Ontology over representation analysis (ORA) showed enrichment in chromatin-related pathways, including nucleosome assembly and DNA packaging, mainly driven by histone H1 to H4 genes. We also analysed two additional studies, a whole-exome sequencing study involving 1313 cases by Halvorsen et al., and a whole-genome sequencing study involving 53 parent-offspring trios by Lin et al., both of which found an enrichment of chromatin regulation genes in OCD.

Conclusion: Chromatin remodeling regulates neuronal differentiation, synaptic gene expression, and immune signaling. Disruptions in these processes may alter neurotransmission and immune responses, contributing to OCD symptoms and their fluctuation with stress or infection. Our findings highlight chromatin dysregulation as a shared mechanism across common and rare OCD variants. This supports a gene environment model and suggests chromatin remodeling as a novel therapeutic target. Further epigenomic research is needed to investigate these potential mechanisms.

Background: Transcription factor (TF)-dependent DNA demethylation is associated with generation of specific DNA methylation profiles in normal cellular development and disease, although only a small fraction of TFs are known to promote DNA demethylation.

Results: Here, we systematically predicted which TFs have DNA-demethylation-promoting activity. Experiments with deletion mutants of the TFs RUNX1 and SPI1 revealed that this activity is associated with a relatively long intrinsically disordered region (IDR). Examination of the IDRs from eight TFs previously confirmed to have such activity revealed that at least one IDR was active in each TF. We constructed a Random Forest classifier based on 25 numeric physicochemical features extracted from length-controlled 26 positive (active) and 32 negative (inactive) IDRs. Four key features- aromaticity, aliphatic index, fractional charge ratio, and side chain hydrophobic density-were identified as the most informative contributors to prediction of positive IDRs. A model based on these features achieved an area under the receiver operating characteristic curve of 0.84, with an optimized decision threshold of 0.303. Applying this model to all TFs, we predicted 959 of 2364 IDRs to be positive, corresponding to 825 of 1308 TFs. The model correctly identified all of 14 previously validated positive TFs. The predicted positive TFs showed significant enrichment of Gene Ontology terms related to morphogenesis and development and may be clinically relevant to certain cancer types.

Conclusion: The developed model with high predictive performance and the predicted TFs with DNA-demethylation-promoting activity will be useful for further analysis of TFs involved in generation of DNA methylation profiles in normal cell development and disease.

Loss-of-function mutations in DNMT3A, a DNA methyltransferase, or NSD1, a histone methyltransferase, cause overgrowth syndromes. Conversely, disruption of the DNMT3A domain that binds NSD1-deposited H3K36 dimethylation (H3K36me2) results in growth restriction. To investigate the molecular basis of these opposing growth outcomes, we generated isogenic human embryonic stem cells carrying growth syndrome-associated mutations in DNMT3A and NSD1. Unexpectedly, both overgrowth- and growth restriction-associated DNMT3A mutations led to DNA hypomethylation in a shared subset of active enhancers, implicating H3K36me2 in directing enhancer methylation maintenance. In contrast, bivalent promoters-marked by both active and repressive histone modifications-showed divergent DNA methylation changes: hypermethylation in growth restriction-associated DNMT3A mutants and hypomethylation in overgrowth-associated DNMT3A or NSD1 loss-of-function mutants. These findings identify locus-specific DNA methylation defects as a common molecular feature and nominate dysregulated DNA methylation at bivalent promoters as a potential driver of abnormal growth phenotypes.

Background: CTCF (CCCTC-binding factor) is the best-studied architectural protein that is highly conserved among animals, including Drosophila and mammals. In Drosophila, CTCF is involved in the organization of functional promoters and insulators, in cooperation with many other architectural proteins, including Su(Hw) and Pita. These proteins, like many other architectural proteins, interact with CP190, which, along with its partners, recruits transcriptional complexes to target promoters. This study was conducted to investigate the cooperation between architectural proteins in the recruitment of CP190 to regulatory elements.

Results: We generated transgenic flies expressing double and triple mutants of dCTCF, Su(Hw), and Pita that cannot interact with CP190. The single mutants are fully viable; however, few triple mutants develop into adults. In the triple mutant, although the CP190 concentration is reduced, the level of gene transcription remains unaltered, suggesting that co-expression of the three mutant proteins is responsible for CP190 instability. ChIP-seq analysis showed that CP190 is required for dCTCF-chromatin binding. In the triple mutant, CP190 demonstrates an almost complete loss of association with the promoters and insulators to which the tested architectural proteins bind; however, these regulatory elements were found to retain their activity.

Conclusions: Architectural proteins cooperate to recruit CP190 to regulatory elements and determine its stability. Despite the important role of CP190 in transcriptional regulation, its functions may be partially performed by partner proteins.

Background: Mutations in tumour suppressor p53 are frequently implied in aggressive progression and metastasis in colorectal cancer. But the distinct phenotypes exhibited by site-specific mutations of p53 are not well elucidated. Here, we investigate the epigenetic and transcriptional impact of three major p53 hotspot mutations (R175H, R273H and R282W), through DNA methylation changes and single cell transcriptomics.

Results: We observed that the p53 R273H mutation is associated with a partial epithelial-mesenchymal transition (pEMT) and increased metastatic progression. Analysis of DNA methylation patterns revealed a distinct epigenetic landscape in R273H-mutant tumours, with hypomethylated regions correlating with enhanced transcriptional activation of YAP/TAZ target genes thus promoting pEMT and EMT-like phenotype in CRC tumours. In vitro ChIP-seq experiments in colorectal cancer cells expressing the R273H mutant p53 (HT29) showed enrichment of mutant p53 at the promoters of YAP/TAZ target genes suggesting EMT/pEMT like states with R273H mutation. Further, simulations from a gene regulatory network incorporating the interactions of p53R273H with EMT regulators explain how this mutation shapes the phenotypic landscape accessible to cancer cells. Our analysis of single-cell transcriptomes of colorectal tumours reveals R273H-linked enrichment of partial and mesenchymal EMT phenotypes across tumour subpopulations in CRC.

Conclusions: We identified a distinct epigenetic signature associated with the p53 R273H mutation, characterised by hypomethylation of YAP/TAZ signalling genes that drives partial EMT and aggressive tumour behaviour. These findings highlight the importance of mutation-specific epigenetic regulation in shaping colorectal cancer progression and the need for developing therapeutic strategies tailored to p53 mutation status.

Endothelial-mesenchymal transition (EndMT) is a biological process in which endothelial cells lose intercellular junctions and endothelial characteristics under specific pathophysiological stimuli and acquire mesenchymal traits. It plays a critical role in cardiac development, tissue fibrosis, tumor metastasis, atherosclerosis, and other diseases. In recent years, growing evidence has demonstrated that epigenetic modifications and post-translational modifications are central to the precise regulation of EndMT initiation and progression. This review systematically elaborates on how epigenetic mechanisms-such as DNA methylation, histone modifications, and non-coding RNAs-as well as post-translational modifications, including protein phosphorylation, acetylation, and ubiquitination, regulate EndMT by modulating key signaling pathways (e.g., TGF-β, Wnt, Notch) and transcription factors (e.g., Snail, Slug, Twist, ZEB1/2). A deeper understanding of these regulatory networks may provide novel diagnostic biomarkers and therapeutic strategies for diseases targeting EndMT.

Background: Steroid hormones drive the transcription of developmental genes by activating distinct sets of enhancers across tissues and developmental contexts, but the mechanisms that target specific enhancers remain incompletely understood, even in model organisms. It has been proposed that selective binding of nuclear receptors occurs at regulatory sites primed by other classes of DNA-binding transcription factors. However, direct studies of cooperation between nuclear receptors and different transcription factors remain limited. A previous study suggested that the GATA family factor SRP/dGATAb primes regulatory sites in S2 Schneider cells for activation by 20-hydroxyecdysone (20E), the principal steroid hormone in Drosophila development. Yet the genome-wide impact of SRP/dGATAb depletion on transcriptional responses to 20E has not been examined.

Results: We investigated the role of SRP/dGATAb in the response of S2 Schneider cells to 20E using SRP/dGATAb depletion via RNA interference. Combined RNA-Seq and ChIP-Seq analyses identified primary targets of SRP/dGATAb that (i) are transcriptionally induced by 20E and (ii) contain binding sites for both EcR and SRP/dGATAb. SRP/dGATAb depletion altered the transcription of different 20E-induced genes in opposite ways. For one subset of 20E-activated genes whose expression decreased upon depletion, SRP/dGATAb regulated active regulatory sites marked by H3K27Ac and enriched with SRP/dGATAb motifs. In these loci, SRP/dGATAb depletion reduced EcR binding at co-bound sites, demonstrating a priming role for this GATA family protein. In contrast, for a second subset of 20E-activated but SRP/dGATAb-suppressed genes (i.e., genes whose expression increased upon SRP/dGATAb depletion), SRP/dGATAb and EcR co-bound sites exhibited undisturbed EcR binding. Notably, the overall level of H3K27 acetylation at these loci increased upon SRP/dGATAb depletion.

Conclusions: Our data indicate that SRP/dGATAb positively regulates 20E-inducible transcription in S2 Schneider cells for some genes, functioning as a priming factor that facilitates EcR recruitment and chromatin acetylation. In contrast, for another subset of 20E-inducible genes, SRP/dGATAb exerts a negative regulatory effect, restraining activity of the regulatory sites.

DNA methylation is a most heritable epigenetic modification. Being a major vegetable crop, pepper (Capsicum spp.) possesses an over 3 Gb genome populated with TEs. This indicates a rich reservoir of epigenetic regulatory mechanisms. However, this large and complex genome renders the study of DNA methylation unaffordable and technically challenging. In this study, we analyzed DNA methylome in Capsicum spp., with a focus on C. annuum ST-8. We found that the genomes of Capsicum spp. are heavily methylated, particularly in the non-CG contexts. This is true when comparing to wheat, whose genome is over 16 Gb, containing over 80% TEs and repeats. Interestingly, we observed genic non-CG methylation and found that it is likely maintained by the CMTs, instead of RdDM. Overall, there is a negative relationship between gene expression and H3K9me2, and a positive relationship between genic non-CG methylation and H3K9me2, despite that genes without genic CHH methylation also possess some H3K9me2. Finally, we performed salt stress treatment with and without priming, and profiled active chromatin features as well as transcriptomes. We found that regardless of the environmental stimuli and developmental stages, the overall negative relationship between transcription and H3K9me2 is stably maintained. Altogether, our study revealed features of DNA methylation in ST-8 and we suggest that these features are likely common in Capsicum spp.