Epigenetics最新文献

Cancer remains a significant barrier to human longevity and a leading cause of mortality worldwide. Despite advancements in cancer therapies, challenges such as cellular toxicity and drug resistance to chemotherapy persist. Regulated cell death (RCD), once regarded as a passive process, is now recognized as a programmed mechanism with distinct biochemical and morphological characteristics, thereby presenting new therapeutic opportunities. Ferroptosis, a novel form of RCD characterized by iron-dependent lipid peroxidation and unique mitochondrial damage, differs from apoptosis, autophagy, and necroptosis. It is driven by reactive oxygen species (ROS)-induced lipid peroxidation and is implicated in tumorigenesis, anti-tumor immunity, and resistance, particularly in tumors undergoing epithelial-mesenchymal transition. Moreover, ferroptosis is associated with ischemic organ damage, degenerative diseases, and aging, regulated by various cellular metabolic processes, including redox balance, iron metabolism, and amino acid, lipid, and glucose metabolism. This review focuses on the role of epigenetic factors in tumor ferroptosis, exploring their mechanisms and potential applications in cancer therapy. It synthesizes current knowledge to provide a comprehensive understanding of epigenetic regulation in tumor cell ferroptosis, offering insights for future research and clinical applications.

Gastric cancer (GC) is one of the most common malignancies with limited treatment options and poor prognosis. Therefore, it is necessary to identify new markers for the development of novel therapeutic strategies. Long non-coding RNAs (lncRNAs) have emerged as pivotal players in cancer. However, RNA-based cancer therapy has been challenged by non-specificity and adverse immune effects. Thus, a comprehensive understanding of the functional roles of lncRNAs and their regulatory networks in downstream pathways may provide more specific targets. In this study, we identified a novel lncRNA, Lnc21q22.11, encoded by the region of chromosome 21q22.11. The full-length transcript was 1202 nt, and its expression was reduced in GC. The expression of Lnc21q22.11 was regulated by histone methylation. Lnc21q22.11 inhibited GC cell proliferation, colony formation, invasion, and migration. Lnc21q22.11 suppressed N87 cell xenograft growth in mice. Mechanistically, Lnc21q22.11 inhibited the mitogen-activated protein kinase kinase/extracellular signal-regulated kinase (MEK/ERK) signaling pathway by interacting with MYH9 in GC cells. Loss of or reduced Lnc21q22.11 expression sensitized GC cells to MEK inhibitor. In conclusion, Lnc21q22.11 is a novel lncRNA in gastric cancer. It suppresses gastric cancer growth by inhibiting the MEK/ERK signaling pathway both in vitro and in vivo.

While genetic studies have provided insights into essential hypertension (EH, defined by high blood pressure ≥140/90 mmHg), investigation through epigenetics may address gaps in understanding its heritability. This study focused on African Brazilian populations in Vale do Ribeira River region, due to their high hypertension prevalence. We aimed to determine if DNA methylation is linked to hypertension susceptibility, through a genome-wide evaluation of 80 peripheral blood samples from normotensive (39) and hypertensive (41) individuals, with Infinium Methylation EPIC BeadChip platform. Data were analyzed using ChAMP package and cross-referenced with information from databases such as EWAS Atlas, GWAS catalog, GeneCards, literature, and tools such as VarElect and EWAS Toolkit. The comparison between hypertensive and normotensive revealed 190 differentially methylated CpG positions (DMPs) and 46 differentially methylated regions (DMRs), both with p-value ≤0.05. Among the DMPs, 27 were found to have a plausible role in blood pressure. Among the DMRs, those mapped to ABAT, BLCAP, CERS3, EIF4E, FMN1, GABBR1, HLA-DQB2, HOXA5, IL5RA, KCNH2, MIR487B, MIR539, MIR886, MKRN3, NUDT12, PON3, RNF39, RWDD3, and TSHBS1 were highlighted because of their lowest p-values, current literature, and/or VarElect prioritization. Our findings suggest that differences in methylation contribute to the high susceptibility to essential hypertension in these populations.

In this article collection, we describe how noncoding epigenetic changes in DNA are transmitted across multiple generations in eukaryotic organisms including plants and animals. And such environmentally induced biochemical alterations of DNA and histones result in profound changes in gene expression. In plants and invertebrate animals, transgenerational epigenetic inheritance has been well documented, and it continues to be substantiated in humans and other vertebrates. These exciting new discoveries have profound consequences for changing as well as maintaining phenotypes expressed by various life forms and, thus, the changes likely contribute to evolution. And in a more practical way, such studies are very important because of the likely transgenerational inheritance of diseases and disorders, such as type 2 diabetes mellitus and obesity.

Recent research highlights the crucial role of muscle-brain crosstalk in metabolic regulation, particularly in individuals with type 2 diabetes and obesity. Myokines, protein hormones secreted by skeletal muscle, play a crucial role in this communication, influencing brain functions such as neuroplasticity, memory, and mood. Specific myokines like cathepsin B, FNDC5/irisin and interleukin-6 have been identified as key players in this muscle-brain axis. Physical activity modulates the production of these molecular factors, enhancing muscle-brain crosstalk and influencing cellular interactions. Moreover, exercise training may lead to adaptive long-term changes in gene expression, mediated by epigenetic regulators. Metabolic pathways activated during exercise can directly impact epigenetic marks by modulating the availability of metabolic intermediates required for these modifications. In the present review, we summarize the latest findings on the association between obesity/diabetes and cognitive impairment due to hippocampal dysfunction, and elaborate on how exercise influences cognitive functions via the communication between skeletal muscle and the brain. We focus on the underlying mechanisms responsible for the muscle-brain crosstalk, emphasizing dynamic changes in the epigenome and epitranscriptome, which sheds light on novel preventive and therapeutic approaches to combat obesity and cognitive decline.

Paternal influence on the offspring epigenome is difficult to interpret in observational human studies due to heterogeneous designs, causing varying susceptibility to bias and non-causal explanations. We conducted a systematic review (CRD42022302695) of paternal exposures before or during pregnancy in relation to the offspring epigenome, focusing on characteristics affecting causal interpretation and reproducibility. We searched three electronic databases for human studies published between 2003 and 2023. Eligible studies assessed paternal factors before or during pregnancy as exposures, and epigenetic mechanisms as outcomes. Risk of bias (RoB) was evaluated using ROBINS-E. The most frequently studied paternal factors were BMI/obesity (7), age (7), smoking (5), and socioeconomic status (SES) (4). All 28 studies assessed DNA methylation; two additionally explored miRNA expression. Most studies were rated 'high' or 'very high' RoB, primarily due to unclear exposure measurement and confounding. Findings showed limited overlap in CpG sites and genomic regions across studies. However, exposures that were stable (e.g. SES) or had clearly defined timing produced more consistent results. Notably, studies with clearly defined timing of paternal smoking suggested preconception exposure may influence offspring epigenetic pathways related to innate immunity but not pregnancy exposure. In contrast, paternal factors with poorly defined experimental analogues, such as BMI, provided inconsistent results. Aligning study design more closely with clinical trials or animal models, by clearly defining populations and exposures, may result in more reliable and replicable findings. Frameworks like 'target trial emulation,' offer a promising approach to improve reproducibility and interpretability of future research on paternal effects on offspring epigenome.

Recent studies have shown that newborns conceived using assisted reproductive technology (ART) exhibited significantly different DNA methylation (DNAm) profiles at birth compared to those conceived naturally. Of note was the observation of increased DNAm at the promoter region of BRCA1/NBR2 in ART-conceived newborns. However, it remains unclear if these DNAm differences persist after birth. Using the Norwegian Mother, Father, and Child Cohort Study (MoBa), a large-scale population-based pregnancy cohort with extensive longitudinal data collected through biological samples and questionnaires, we generated longitudinal DNAm data for 105 ART-conceived and 250 naturally conceived children at birth and at ages 3-22 years. DNAm differences in the BRCA1/NBR2 promoter between ART- and naturally conceived children, at birth and postnatally, were tested using linear mixed model with adjustment for maternal and newborn covariates. While ART-conceived children showed subtle hypermethylation at birth and postnatally, the differences diminished over time and did not remain statistically significant after multiple testing correction. Our findings suggest that subtle hypermethylation at the BRCA1/NBR2 promoter in ART-conceived children may represent an ART-associated epigenetic signature, although further studies in larger populations are needed to clarify its persistence and significance.

Epigenetic changes are implicated in development, repair, and physiology of postnatal skeletal muscle (SkM). We generated methylomes for human myoblasts (SkM progenitor cells) and determined myoblast differentially methylated regions (DMRs) for comparison to the epigenomics and transcriptomics of diverse cell types. Analyses were from global genomic and single-gene perspectives and included reporter gene assays. One atypical finding was the association of promoter-adjacent hypermethylation in myoblasts with transcription turn-on, but at downmodulated levels, for certain genes (e.g., SIM2 and TWIST1). In contrast, brain-specific OLIG2 was in repressed chromatin and silent in most cell types but linked to hypermethylated DMRs specifically in myoblasts. The OLIG2-linked DMRs might be needed because of the overlapping or nearby binding of myogenic differentiation protein 1 (MYOD). We found genome-wide overlap of DMRs with MYOD or CCCTC-binding factor (CTCF) binding sites in myoblasts that is consistent with the importance of MYOD, as well as CTCF, in organizing myoblast transcription-enhancing chromatin interactions. We also observed some gene upregulation correlated with a special association of regional DNA hypomethylation with H3K36me3, H3K27ac, and H3K4me1 enrichment. Our study highlights unusual relationships between epigenetics and gene expression that illustrate the interplay between DNA methylation and chromatin epigenetics in the regulation of transcription.

DNA methylation is a common epigenetic modification that maintains the integrity of the DNA sequence while profoundly influencing gene expression and phenotypic variation. Aberrant DNA methylation has been associated with the onset and progression of diseases, including cancer, metabolic disorders, and neurodevelopmental disorders. Recent advancements in detection technology led to a gradual increase in the exploration of DNA methylation as a valuable biomarker for cancer diagnosis and therapy. Single-base resolution has been achieved for whole-genome methylation analyses through second-generation sequencing technology, significantly enhancing detection efficiency. Additionally, PCR-based methods offer simple and feasible solutions for methylation analysis. In this review, we discuss various methods for detecting DNA methylation, focusing on bisulfite conversion-based techniques, methylation-sensitive restriction enzyme methods, enzyme conversion-based methods, third-generation sequencing approaches, and artificial intelligence. Furthermore, we briefly summarize the methylation biomarkers used for tumor diagnosis and the corresponding sample types employed. We believe that this information provides valuable insights for selecting and optimizing DNA methylation analysis tools.