Epigenetics & Chromatin最新文献

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.

ING5, initially identified as a tumor-suppressor, serves as a chromatin regulator with a diverse and extensive range of biological functions. This review undertakes an in-depth exploration of the structural characteristics and domain organization of ING family proteins, with a specific emphasis on ING5. The functional characteristics of ING5 are highly intricate and multi-dimensional. In the context of chromatin regulation and gene expression control, ING5 engages in interactions with diverse protein complexes through its conserved domains. It actively participates in the fine-tuning of chromatin structure and gene expression within tumor cells. Moreover, ING5 plays a pivotal and indispensable role in the regulation of DNA replication, cell cycle, and apoptosis, thereby exerting a profound influence on the fundamental biological processes of cells. Additionally, the binding properties and genomic associations of ING5 contribute significantly to its wide-ranging functions. ING5 exerts multiple and intricate action mechanisms in the processes of tumorigenesis, tumor development, and cancer treatment. It has substantial impacts on the biological behaviors of tumor cells, including proliferation, migration, and invasion. Furthermore, ING5 has emerged as a highly promising target for cancer therapy, presenting novel opportunities for the development of tumor-specific treatment strategies. Beyond its well-established role in tumor suppression, ING5 exhibits a diverse array of physiological functions. In the context of stem cell differentiation, ING5 regulates gene expression patterns, which are of utmost importance for determining cell fate. During embryonic development, it ensures the normal expression of genes associated with cell proliferation and differentiation, thereby being essential for the proper morphogenesis of the embryo. ING5 is also involved in metabolic regulation, particularly lipid metabolism, by modulating relevant genes to influence lipid levels. Additionally, it participates in the maintenance of vascular function by regulating the activities of vascular endothelial cells and angiogenesis, which are crucial for vascular homeostasis. This review comprehensively summarizes the extensive functions of ING5 as an epigenetic regulator in maintaining physiological homeostasis. By delving into its roles beyond tumor suppression, we aspire to attain a more comprehensive and in-depth understanding of its significance and potential implications in various biological processes and medical applications.

Background: Protamines play a crucial role in nuclear condensation during spermiogenesis, a process associated with significant chromatin remodeling and replacement of histones. While much research has focused on the function of protamines in sperm development and fertility, their effects in non-sperm cells remain largely unexplored. Protamines are increasingly used in the clinical setting, and understanding better, the role of protamines in somatic cells remains a critical unmet need.

Results: In this study, we investigated the impact of overexpressing murine and human protamine 1 and 2 (PRM1 and PRM2) on nuclear architecture, histone eviction, DNA methylation, and transcription in HEK293T cells and mesenchymal stromal cells (MSCs). Overexpression of protamines resulted in nuclear condensation; particularly PRM1 showed notable enrichment in nucleoli, and cells exhibited cell cycle abnormalities. Immunofluorescence staining indicated a significant reduction in specific histone modifications (H3K9me3, H3K4me1, and H3K27Ac) in response to protamine expression, especially in MSCs. Interestingly, despite these changes in nuclear organization, the methylome remained largely stable. However, expression of protamines significantly diminished transcription, particularly of the ribosomal genes, upon PRM1 expression.

Conclusions: Our studies indicate that PRM1 and PRM2 may bind to and condense distinct genomic regions in somatic cells, resulting in widespread silencing of gene expression, while retaining a largely stable DNA methylome.

Background: Epigenetic modifications, nucleosome occupancy, and three-dimensional chromatin architecture collectively create a multi-layered, highly interactive regulatory system for controlling genomic functionality. Dysregulation of epigenetic processes leads to a plethora of abnormalities including disease states. Therapies focused on epigenetic modulation can alter gene expression to correct dysfunction, though the perpetuation of these states and the relationships among chromatin regulatory layers is not well understood.

Results: Here, we investigated global and local chromatin structural and functional responses after acute histone deacetylase inhibitor treatment (suberoylanilide hydroxamic acid) in lung cancer cells across time. Treatment substantially increased global histone acetylation resulting in a pervasive but not distinctive signature. The spread of acetylation did not significantly impact global chromatin accessibility, and nucleosome remodeling largely occurred at finer scales in functionally relevant genomic regions. Indeed, both H3K4 trimethylation, a mark of active transcription, and gene expression changes were altered in a controlled locus-specific manner, suggesting aberrant acetylation indirectly leads to balanced and bidirectional gene expression profiles from tighter regulation of other chromatin features. HDACi treatment induced (13%) genomic rearrangement in chromatin compartmentalization and moderate weakening of topologically associating domains.

Conclusions: Continuous wavelet analysis of these features demonstrates that scale-dependent, locus-specific factors influence the relationship between chromatin architecture and functional output, suggesting that regulation of transcription and nucleosome remodeling is not entirely (nor linearly) dependent upon large scale compartment exchange. Structural and functional responses are most pronounced early after treatment with partial persistence of differential local chromatin features and expression later in time; this highlights the plasticity of chromatin regulation, which may have implications for the efficacy of epigenetic treatments. These results demonstrate the effectiveness of multi-layered regulation of transcription: in resilient systems, disruption of one chromatin feature does not distort the regulation of other features in supporting a transcriptional program that allows for survival.

The transcription of satellite DNA is highly sensitive to environmental factors and represents a source of genomic instability. Therefore, tight regulation of (peri)centromeric transcription is essential for genome maintenance. Antibiotics are routinely used for in vitro studies and for medical treatment, however, their effect on pericentromeric satellite DNA transcription was not investigated. Here we show that antibiotics geneticin and hygromycin B, conveniently used in cell culture, as well as rifampicin (along with five other antibiotics), used to treat bacterial infections, increase transcription of a major human pericentromeric alpha satellite DNA in cell lines at standard concentrations. However, response differs among cell lines - maximal increase in A-1235 cells is obtained by rifampicin while in HeLa cells and fibroblasts by geneticin. There is also a positive correlation between antibiotic concentration and the level of alpha satellite transcription. The increase of transcription is accompanied with either H3K9me3 decrease or H3K18ac increase at tandemly arranged alpha satellite arrays while H3K4me2 remains unchanged. Our results suggest that induced alpha satellite DNA transcription upon antibiotic stress could be linked to epigenetic changes - histone modifications H3K9me3 and H3K18ac, which are associated with transcription of heterochromatin.