Epigenetics & Chromatin最新文献

Background: Bmi1, a key component of the Polycomb repressive complex 1, plays a critical role in regulating gene expression by modulating chromatin structure. Its depletion is known to cause hair cell loss in the neonatal mouse cochlea. This study aimed to investigate the epigenetic mechanisms and transcriptional consequences of Bmi1 depletion in the neonatal auditory sensory epithelium.

Results: Analysis of neonatal Bmi1 knockout mice using H3K27me3 chromatin immunoprecipitation sequencing, assay for transposase-accessible chromatin sequencing, and RNA sequencing revealed significant transcriptional alterations, particularly in genes governing cell proliferation, senescence, and death. Bmi1 depletion resulted in widespread gene upregulation and increased chromatin accessibility, which correlated with reduced H3K27me3 enrichment. Notably, expression of Cdkn2c, a key cell cycle regulator, was significantly upregulated. Inhibition of Cdkn2c rescued the proliferative capacity of inner ear epithelial cells in Bmi1 knockout mice.

Conclusions: These findings demonstrate that Bmi1 maintains transcriptional repression and chromatin state in the developing cochlea, primarily through H3K27me3 deposition. Depletion disrupts this control, leading to Cdkn2c overexpression and impaired cell proliferation. This identifies Cdkn2c and its regulatory pathway as potential therapeutic targets for hearing loss associated with hair cell depletion.

Background: Nucleosome ubiquitination at lysine 119 of histone H2A (H2AK119ub) and lysine 120 of histone H2B (H2BK120ub) are prominent post-translational modifications with opposing roles in chromatin regulation. Although H2AK119ub is associated with transcriptional repression and H2BK120ub with activation, the molecular basis for these contrasting effects has remained unclear.

Results: Here, we use microsecond all-atom and millisecond coarse-grained molecular dynamics simulations to reveal how the position of ubiquitin reshapes nucleosome structure and assembly. H2AK119ub rigidifies the histone core by indirectly reinforcing the L1-L1 interface between H2A histones, strengthening both tetramer-dimer and dimer-dimer interactions, and slowing complete nucleosome assembly. In contrast, H2BK120ub disrupts these interfaces, weakens the histone core, and favors partially assembled hexasome and tetrasome states. Both modifications cause dramatic slowdowns in nucleosome folding, with H2BK120ub producing an order-of-magnitude greater effect. These simulations establish clear molecular mechanisms by which site-specific ubiquitination alters nucleosome stability and assembly kinetics.

Conclusion: Our findings quantitatively explain how H2A and H2B ubiquitination exert opposing effects on chromatin regulation. This mechanism is directly relevant to the opposing roles of these marks in transcriptional activation and repression, and may represent one way that combinations of histone modifications modulate chromatin function in vivo.

5-hydroxymethylcytosine (5hmC), an epigenetic modification derived from the oxidation of 5-methylcytosine (5mC) by the ten-eleven translocation (TET) family of dioxygenases, plays a pivotal role in the regulation of gene expression, cellular differentiation, and developmental plasticity. Once considered an intermediate in DNA demethylation, 5hmC is now recognized as a stable and functionally significant epigenetic mark with distinct genomic distributions and significant regulatory implications. This review provides a comprehensive analysis of the biological functions of 5hmC in normal cellular processes, including its role in maintaining tissue-specific gene expression, lineage commitment, and genomic integrity. We also describe its role in cancer, the mechanistic underpinnings of its loss or redistribution in tumor cells, and how these changes contribute to oncogenic signaling pathways, epithelial-mesenchymal transition, and tumor heterogeneity. Furthermore, we explore the utility of 5hmC as a biomarker in cancer diagnostics and prognostics, supported by recent advances in sequencing technologies and cell-free DNA profiling. We also examine the intersection of 5hmC and chemotherapy, highlighting how aberrant 5hmC levels can influence drug resistance and sensitivity, and assess the therapeutic potential of targeting TET enzymes and associated pathways. By integrating insights from basic epigenetics, cancer biology, and therapeutic research, this review underscores the multifaceted role of 5hmC in human malignancies and outlines the translational opportunities for exploiting 5hmC-related mechanisms in precision oncology.

Background: Flatfish metamorphosis involves dramatic tissue remodeling, including the migration of one eye to the opposite side of the body, enabling the transition from pelagic to benthic life. While this process requires precise transcriptional regulation, the role of epigenetic mechanisms remains poorly understood. Here, we investigate DNA methylation dynamics during turbot metamorphosis using reduced-representation bisulfite sequencing (RRBS) across three key stages: pre-metamorphosis, climax, and post-metamorphosis.

Results: We identified stage-specific methylation patterns, with more than 31% of hypermethylated regions emerging during the climax phase-coinciding with upregulated dnmt3a (de novo methyltransferase) and altered expression of photoreceptor adaptation genes. Critically, the migrating and non-migrating eyes exhibited divergent methylation and expression of retinal ganglion cell (RGC) regulators (eomesa, tbr1b), linking epigenetic changes to asymmetric ocular development.

Conclusion: Our results suggest that DNA methylation may play a role in visual system remodeling, particularly in processes associated with RGC-mediated eye migration and light-sensing adaptation, providing new understanding of the epigenetic regulation of vertebrate metamorphosis.

The expansion of adipose tissue during obesity results in alterations in the expression of adipose-derived hormones or factors, which control whole-body energy metabolism. Epigenetics refers to the heritable modifications in gene function that arise without changes in DNA sequence and are sculped by environmental factors, lifestyles, and nutritional variables. DNA methylation is a well-characterized epigenetic mechanism, and altered expression of adipose-derived hormones or factors is partly ascribed to alterations in DNA methylation levels or patterns. This review aims to summarize the regulatory effects of DNA methylation on the expression of adipokines and adipose factors, including leptin, adiponectin, cytokines as well as insulin-like growth factors (IGFs) and IGF-binding proteins (IGFBPs) under obese conditions. The feasibility of DNA methylation as a biomarker for the prediction and prognosis of obesity and type 2 diabetes (T2D) would be also discussed.

Background/purpose: Sjögren's syndrome (SS) is a chronic systemic autoimmune disease characterized by lymphocytic infiltration and formation of lymphoepithelial lesions (LEL) in exocrine glands, leading to secretory dysfunction. DNA methylation, a dynamically regulated epigenetic mark, has been increasingly recognized as a key regulatory mechanism in the pathogenesis of autoimmune diseases including SS, and holds promise for identifying novel diagnostic and therapeutic strategies.

Methods: Reduced representation bisulfite sequencing (RRBS) was performed on 4 cases of SS and 3 controls to profile genome-wide DNA methylation patterns. Differentially methylated regions (DMRs) and associated differentially methylated genes (DMGs) were detected, followed by functional enrichment analysis. Integration with transcriptomic data (GSE40611) was performed to identify overlapping epigenetic and transcriptional changes.

Results: A total of 29,462 DMRs were detected, with 24,116 hypermethylated and 5,346 hypomethylated regions, indicating an overall increase in methylation levels of SS, and DMGs located in gene promoter regions were significantly enriched in pathways related to immune response, transcriptional regulation, and inflammation. Nine hub genes (LCP2, BTK, LAPTM5, ARHGAP9, IKZF1, WDFY4, CSF2RB, ARHGAP25, DOCK8) were identified, which displayed promoter hyper-or hypomethylation, indicating the complex epigenetic regulatory mechanisms.

Conclusion: This study reveals extensive DNA methylation alterations in SS, providing new insights into the epigenetic mechanisms underlying pathogenesis. Moreover, these findings suggest potential biomarkers or therapeutic targets for further investigation to elucidate detailed molecular mechanisms of SS.

Background: Genetic ancestry is an important factor to account for in DNA methylation studies because genetic variation influences DNA methylation patterns. One approach uses principal components (PCs) calculated from CpG sites that overlap with common SNPs to adjust for ancestry when genotyping data is not available. However, this method does not remove technical and biological variations, such as sex and age, prior to calculating the PCs. The first PC is therefore often associated with factors other than ancestry.

Methods: We developed and adapted the adapted EpiAnceR+ approach, which includes (1) residualizing the CpG data overlapping with common SNPs for control probe PCs, sex, age, and cell type proportions to remove the effects of technical and biological factors, and (2) integrating the residualized data with genotype calls from the SNP probes (commonly referred to as rs probes) present on the arrays, before calculating PCs and evaluated the clustering ability and relationship to genetic ancestry.

Results: The PCs generated by EpiAnceR+ led to improved clustering for repeated samples from the same individual and stronger associations with genetic ancestry groups predicted from genotype information compared to the original approach. EpiAnceR+ also outperformed the use of DNA methylation PCs or surrogate variables for ancestry adjustment.

Conclusions: We show that the EpiAnceR+ approach improves the adjustment for genetic ancestry in DNA methylation studies. EpiAnceR+ can be integrated into existing R pipelines for commercial methylation arrays, such as 450 K, EPIC v1, and EPIC v2. The code is available on GitHub ( https://github.com/KiraHoeffler/EpiAnceR ).

Background: Although liquid-liquid phase separation (LLPS) proteins are known to participate in genome organization and transcriptional regulation through the formation of biomolecular condensates, their functional interplay with other regulatory proteins and histone modifications in chromatin loop formation remains poorly characterized. By combining Hi-C chromatin interaction data with ChIP-seq profiles of 12, 27, and 24 LLPS proteins in GM12878, K562, and HepG2 cell lines, respectively, we identified chromatin loops associated with LLPS proteins and systematically analysed patterns of cooperative protein binding and histone modification enrichment within these loop-associated peaks.

Results: We identified 162, 313, and 431 chromatin loops associated with LLPS proteins in GM12878, K562, and HepG2 cell lines, respectively. These loops were relatively small in size and predominantly anchored at enhancer regions. Examination of cooperative binding of proteins within loop-associated peaks revealed that transcriptional repressor IKZF1, HDAC1, and SAP130 most frequently co-localized with LLPS proteins in GM12878, K562, and HepG2 cells, respectively. Further analysis of histone modification enrichment patterns revealed that active histone modifications, such as H3K4me2, H3K4me3, H3K9ac, and H3K27ac, co-localized at loop-associated peaks, with H3K4me1 exhibiting additional specific co-localization with these four histone modifications at enhancer-localized loop-associated peaks. Notably, bivalent chromatin domains where H3K27me3 co-localized with active histone modifications were identified at promoter-localized loop-associated peaks in HepG2 cells, and elevated H3K27me3 occupancy at these peaks was associated with transcriptional repression of target genes. Moreover, quantitative RNA-seq analysis revealed that the expression of target genes associated with enhancer-promoter loops was correlated with both the binding of LLPS proteins and the enrichment patterns of histone modifications within their ChIP-seq peaks at loop anchors.

Conclusions: Our study suggests that LLPS proteins may cooperate with transcriptional repressors to facilitate chromatin looping. Furthermore, local enrichment of histone modifications at loop-associated peaks provides additional regulatory control over chromatin architecture and gene transcription.

Background: Histone Post-Translational Modifications (PTMs) are important epigenetic marks, whose specific pattern over the chromatin plays a critical role in turning the corresponding gene on/off. During DNA replication in mitotic cells, the histone PTMs are dislodged from the mother chromatid, ahead of the replication fork, and distributed uniformly at random among the daughter chromatids. We show that maintaining the fidelity of a primary PTM pattern, from the partial information available after replication, can be significantly improved by the presence of an additional antagonistic PTM sequence in the mother.

Results: Building on our previous study which proposed mechanisms for maintaining fidelity by utilizing only half the parental nucleosomes, the current work considers the effect of an additional antagonistic PTM sequence. We represent the joint PTM sequence by an appropriate Markov model and the DNA replication fork as a noisy communication channel. An optimal Bayesian sequence estimator is then employed at each of the daughter chromatids to reconstruct the primary PTM pattern. A high-fidelity reconstruction, potentially aided by the enzyme machinery, is shown to be possible in the presence of epigenetic memory. The structural properties derived for the optimal estimator are then verified through simulations, which show the improvement in fidelity of inheritance with antagonism. This is further supported empirically through observations from some recent experimental data CONCLUSIONS: Our work provides a computational model to quantify the effect of combinatorial histone PTMs in epigenetic inheritance. The fidelity of reconstruction of the primary histone PTM post-replication, is shown to be enhanced in the presence of antagonistic PTMs in the vicinity.

Environmental changes can induce epigenetic modifications, influencing gene expression, phenotype, and species adaptation. This study investigates how temperature affects genome-wide DNA methylation patterns, particularly in genes crucial for sex development and whether these modifications can be transmitted across generations. Using the European sea bass -a fish model with both genetic and environmental sex determination- we analyzed DNA methylation at single nucleotide resolution using reduced representation bisulfite sequencing in 64 individuals from five families across two generations (F0 and F1). Parental fish (F0) were exposed to either control (16 °C, C) or elevated (21 °C, T) temperatures from 12 to 60 days post-fertilization. Their offspring (F1) were then subjected to four thermal regimes: control (CC), ancestral exposure via sires (TC), developmental exposure in offspring (CT), and dual exposure (TT). We determined the length of differentially methylated regions (DMRs) using a conservative, reproducible, and species-specific method adapted from plant epigenetics. To disentangle ancestral and developmental temperature effects, DMRs were classified according to their association with F0, F1, or F0 x F1 interaction effects. This allowed us to quantify the relative contribution of each treatment, separately for testes and ovaries in the F1 generation. While the proportion of additive DMRs showing cumulative temperature effects (e.g., 2.1% in testes, 1.4% in ovaries) was relatively rare, a substantial proportion of DMRs (37% in testes, 31.1% in ovaries), exhibited opposing methylation changes with F0 and F1 treatments, indicative of compensatory epigenetic interactions. These interactions were also reflected at the phenotypic level: TT individuals showed body weights comparable to CC, and the sex ratio in TT approached statistical significance when compared to CC (P = 0.051), suggesting a link between epigenetic regulation and phenotypic plasticity under elevated temperatures. Finally, we also investigated the inheritance of epimarks from sires to offspring. While most epimarks remained stable across generations, ~ 5% of all DMRs were both temperature-induced and inherited, offering direct evidence for environmentally responsive multigenerational epigenetic inheritance. This study demonstrates the role of temperature in shaping the epigenome and highlights the potential of epigenetic plasticity and inheritance in species adaptation and conservation amid global warming.