Epigenomes最新文献

The skin, the largest organ of the human body, plays numerous essential roles, including protection against environmental hazards and the regulation of body temperature. The processes of skin homeostasis and ageing are complex and influenced by many factors, with epigenetic mechanisms being particularly significant. Epigenetics refers to the regulation of gene expression without altering the underlying DNA sequence. The dynamic nature of the skin, characterized by constant cellular turnover and responsiveness to environmental stimuli, requires precise gene activity control. This control is largely mediated by epigenetic modifications such as DNA methylation, histone modification, and regulation by non-coding RNAs. The present review endeavours to provide a comprehensive exploration and elucidation of the role of epigenetic mechanisms in regulating skin homeostasis and ageing. By integrating our current knowledge of epigenetic modifications with the latest advancements in dermatological research, we can gain a deeper comprehension of the complex regulatory networks that govern skin biology. Understanding these mechanisms also presents promising avenues for therapeutic interventions aimed at improving skin health and mitigating age-related skin conditions.

Rheumatoid arthritis (RA) is a progressive autoimmune disease leading to structural and functional joint damage and, eventually, to physical disability. The pathogenesis of the disease is highly complex and involves interactions between fibroblast-like synoviocytes (FLSs) and immune cells, which stimulate the secretion of pro-inflammatory factors, leading to chronic inflammation. In recent years, studies have demonstrated the importance of epigenetics in RA. Specifically, epigenetic alterations have been suggested to serve as diagnostic and treatment biomarkers, while epigenetic mechanisms are thought to be involved in the pathogenesis of RA. Epigenetic regulators coordinate gene expression, and in the case of inflammatory diseases, they regulate the expression of a broad range of inflammatory molecules. In this review, we discuss current evidence on the involvement of DNA and RNA methylation in RA.

Background: Heavy alcohol consumption (HAC) has a profound adverse effect on human health. Unfortunately, there is a relative lack of tools that are easily implementable in clinical settings and that can be used to supplement self-reporting in the diagnosis and management of HAC. In part, this paucity is due to limitations of currently available biological measures and a mismatch between available biological measures and the needs of clinicians managing HAC.

Objectives: We first review the pros and cons of existing biological measures. Next, we review the underlying theory and the performance characteristics of two recently developed methylation-sensitive digital PCR (MSdPCR) assays, referred to as the Alcohol T Score (ATS) and ZSCAN25, for the assessment of chronic and recent HAC, respectively. Finally, we outline a paradigm for improving the clinical diagnosis and management of alcohol use disorders by utilizing these new markers of alcohol consumption.

Conclusions: We conclude that further studies to understand the test performance characteristics of each of these epigenetic tools in larger, diverse populations are in order.

Background/Objectives: People with HIV (PWH) on antiretroviral therapy (ART) often gain weight, which increases their risk of type 2 diabetes and cardiovascular disease. The role of DNA methylation (DNAm) markers in obesity among PWH is understudied. This research explores the relationship between body mass index (BMI) and epigenetic patterns to better understand and manage obesity-related risks in PWH. Methods: We conducted an epigenome-wide association study (EWAS) on 892 African American male PWH from the Veterans Aging Cohort Study, examining BMI associations with DNAm using linear mixed models, adjusting for covariates, including soluble CD14. We compared our results with BMI-associated DNAm markers from non-HIV individuals and developed a methylation risk score (MRS) for BMI using machine learning and a cross-validation approach. Results: We identified four epigenome-wide significant CpG sites, including one in the RAP1B gene, indicating shared and unique BMI-related epigenetic markers between PWH and non-HIV individuals. The constructed BMI MRS explained approximately 19% of the BMI variance in PWH. Conclusions: DNAm markers and MRS are significantly linked to BMI in PWH, suggesting shared and distinct molecular mechanisms with non-HIV populations. These insights could lead to targeted interventions to reduce cardiometabolic disease risks in PWH under ART.

Background/Objectives: Early weaning management followed by energy supplementation can lead to metabolic alterations in the calf that exert long-term effects on the animal's health and performance. It is believed that the main molecular basis underlying these metabolic adaptations are epigenetic mechanisms that regulate, activate, or silence genes at different stages of development and/or in response to different environmental stimuli. However, little is known about postnatal metabolic programming in Bos indicus. Therefore, this study aimed to compare the DNA methylation profile of Nellore animals submitted to conventional and early weaning and to correlate the findings with genes differentially expressed in the Longissimus thoracis skeletal muscle of Bos indicus cattle. Methods: For this, we used Reduced Representation Bisulfite Sequencing (RRBS) and RNA-Sequencing techniques to prospect differentially methylated genes (DMGs). Results: A total of 481 differentially methylated regions were identified, with 52% (250) being hypermethylated and 48% (231) hypomethylated. Functional enrichment analysis of 53 differentially methylated and differentially expressed genes was performed. The main enriched terms and pathways were associated with 3'-5'-cyclic adenosine monophosphate (cAMP) signaling, which presents the upregulated adenylate cyclase 3 (ADCY3) gene and significatively hypomethylated in the promoter region. Alterations in cAMP signaling are involved in numerous processes, many of them related to lipid metabolism. The relative differential expression of key genes of this pathway demonstrates the relationship between cAMP signaling and de novo lipogenesis. Conclusions: These findings suggest an important role of postnatal metabolic programming through DNA methylation mechanisms in determining fat deposition in beef.

Background/objectives: The dynamic interaction between genomic DNA, epigenetic modifications, and phenotypic traits was examined in identical twins. Environmental perturbations can induce epigenetic changes in DNA methylation, influencing gene expression and phenotypes. Although DNA methylation mediates gene-environment correlations, the quantitative effects of external factors on DNA methylation remain underexplored. This study aimed to quantify these effects using a novel approach.

Methods: A cohort study was conducted on healthy monozygotic twins to evaluate the influence of environmental stimuli on DNA methylation. We developed the Environmental Factor Index (EFI) to identify methylation sites showing statistically significant changes in response to environmental stimuli. We analyzed the identified sites for associations with disorders, DNA methylation markers, and CpG islands.

Results: The EFI identified methylation sites that exhibited significant associations with genes linked to various disorders, particularly cancer. These sites were overrepresented on CpG islands compared to other genomic features, highlighting their regulatory importance.

Conclusions: The EFI is a valuable tool for understanding the molecular mechanisms underlying disease pathogenesis. It provides insights into the development of preventive and therapeutic strategies and offers a new perspective on the role of environmental factors in epigenetic regulation.

We aimed to explore the age-dependent epigenetic variability on the X-chromosome with consideration of X-chromosome inactivation by applying a sex-stratified regression analysis to DNA methylation array data on X-linked CpGs in aging identical twins. We found 13 X-linked CpGs showing age-related significant increase in variability in males (FDR < 0.05) but none in females. In females, we found a significantly higher proportion of CpGs showing increased variability with age among nominally significant (p < 0.05) CpGs under inactivation, but not among CpGs escaping inactivation. Survival analysis showed a slight trend of correlation by directional change in the variable CpGs with mortality in males. Compared with females, the male X-chromosome can be more vulnerable to epigenetic instability during aging.

Cryptic transcription refers to the unintended expression of non-canonical sites within the genome, producing aberrant RNA and proteins that may disrupt cellular functions. In this opinion piece, I will explore the role of histone modifications in modulating cryptic transcription and its implications for gene expression and cellular integrity, particularly with a focus on H3K36 and H3K4 methylation marks. H3K36 tri-methylation plays a crucial role in maintaining chromatin integrity by facilitating the recruitment of the Rpd3S histone deacetylase (HDAC) complex, which helps restore closed chromatin states following transcription and prevents cryptic initiation within gene bodies. In parallel, crosstalk between H3K4 di-methylation and histone ubiquitylation and sumoylation is critical for recruiting the Set3 HDAC complex, which maintains low histone acetylation levels in gene bodies and further suppresses cryptic transcription. Therefore, by elucidating these regulatory mechanisms, this opinion highlights the intricate interplay of histone modifications in preserving transcriptional fidelity and suggests potential pathways for future research to develop novel therapies for age-related disorders and other diseases associated with dysregulated gene expression.

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies, characterized by its aggressive progression and dismal prognosis. Advances in epigenetic profiling, specifically DNA methylation analysis, have significantly deepened our understanding of PDAC pathogenesis. This review synthesizes findings from recent genome-wide DNA methylation studies, which have delineated a complex DNA methylation landscape differentiating between normal and cancerous pancreatic tissues, as well as across various stages and molecular subtypes of PDAC. These studies identified specific differentially methylated regions (DMRs) that not only enhance our grasp of the epigenetic drivers of PDAC but also offer potential biomarkers for early diagnosis and prognosis, enabling the customization of therapeutic approaches. The review further explores how DNA methylation profiling could facilitate the development of subtype-tailored therapies, potentially improving treatment outcomes based on precise molecular characterizations. Overall, leveraging DNA methylation alterations as functional biomarkers holds promise for advancing our understanding of disease progression and refining PDAC management strategies, which could lead to improved patient outcomes and a deeper comprehension of the disease's underlying biological mechanisms.

Background: Flowers are important plant organs, and their development is correlated with yield in woody fruit trees. For Pyrus pyrifolia cultivar 'Sucui 1', the research on how DNA methylation accurately regulates the expression of TFs and affects the specific regulatory mechanism of flower bud wizening will help reduce wizened buds.

Methods: Here, the DNA methylomes and transcriptomes of two types of flower buds from the Pyrus pyrifolia cultivar 'Sucui 1' were compared.

Results: 320 differentially expressed transcription factors (TFs), in 43 families, were obtained from the wizened bud transcriptome versus the normal bud transcriptome. Most were members of the AP2/ERF, bHLH, C2H2, CO-like, MADS, MYB, and WRKY families, which are involved in flower development. As a whole, the methylation level of TFs in the 'Sucui 1' genome increased once flower bud wizening occurred. A cytosine methylation analysis revealed that the methylation levels of the same gene regions in TFs from two kinds of buds were similar. However, differentially methylated regions were found in gene promoter sequences. The combined whole-genome bisulfite sequencing and RNA-Seq analyses revealed 162 TF genes (including 164 differentially methylated regions) with both differential expression and methylation differences between the two flower bud types. Among them, 126 were classified as ^mCHH-type methylation genes. Furthermore, the transcriptional down regulation of PpbHLH40, PpERF4, PpERF061, PpLHW, PpMADS6, PpZF-HD11, and PpZFP90 was accompanied by increased DNA methylation. However, PpbHLH130, PpERF011, and PpMYB308 displayed the opposite trend. The expression changes for these TFs were negatively correlated with their methylation states.

Conclusions: Overall, our results offer initial experimental evidence of a correlation between DNA methylation and TF transcription in P. pyrifolia in response to bud wizening. This enriched our understanding of epigenetic modulations in woody trees during flower development.