Epigenetics reports最新文献

Nuclear paraspeckles are membrane-less protein-protein and protein-RNA condensates that assemble co-transcriptionally upon the expression of long non-coding RNA NEAT1. While efforts in the past two decades extensively characterized the components and structures of nuclear paraspeckles, their biochemical, cellular, and physiological functions remain largely unclear. Emerging evidence has revealed that paraspeckles physically interact with active chromatin and promote its establishment, implicating the role of paraspeckles as a functional hub to maintain the active state of chromatin. Here, we discuss recent advances and key knowledge gaps in the biology of paraspeckles, including their interplay with active chromatin, disease associated mutations, and functional discrepancies between mouse and human systems.

In mammals, dosage compensation between the sexes is mediated by X chromosome inactivation. The long non-coding Xist RNA initiates this process. The molecular mechanism of X-linked gene silencing is beginning to be understood. We have previously reported that the cyclin-dependent kinase CDK8 is required for gene silencing and histone H3 trimethyl-lysine 27 recruitment by Xist. CDK8 functions in cell signalling and transcriptional regulation, in particular, it associates with MED12, MED13, and cyclin C to form a kinase submodule of the Mediator complex. It remains unknown if CDK8 acts as a Mediator kinase in X chromosome inactivation. Here, we analyse a Med12 mutation in an embryonic stem cell model for the initiation of X chromosome inactivation. Loss of Med12 is compatible with self-renewal and survival of mouse embryonic stem cells, but impairs X-linked gene silencing by Xist. In addition, recruitment of CIZ1 and histone H3 trimethyl-lysine 27 by Xist are significantly reduced in the absence of Med12. We further show that CIZ1 recruitment is also modulated by Cdk8. Our study shows that mutations of Med12 and Cdk8 have similar effects on Xist function and provide a cell system for studying the role of the Mediator kinase module in X chromosome inactivation.

The enzyme KDM1A encoded by KDM1A and also known as lysine-specific demethylase 1 (LSD1) plays important roles in the development and function of the brain. Vafidemstat is a KDM1A inhibitor that has shown beneficial effects in preclinical and clinical trials for the treatment of neuropsychiatric disorders, including borderline personality disorder (BPD), autism spectrum disorder (ASD), and attention-deficit hyperactivity disorder (ADHD). This article reviews available preclinical and clinical data on the use of vafidemstat in the treatment of these disorders. Vafidemstat appears to be a potential new and safe drug for the treatment of these disorders.

Extracellular vesicle and particle microRNAs (EVP miRNA) in milk have the capacity to facilitate maternal-infant communication in the postpartum period and are hypothesized to play important roles in child development. Maternal diet quality has been linked to milk macronutrient composition, microbiota profiles, as well as various child health outcomes. The aim of this study was to assess the association between maternal diet quality and milk EVP miRNA. In a pilot study of 54 participants from a larger birth cohort study, diet quality was measure by the Alternative Healthy Eating Index 2010 (AHEI-2010) during the second trimester of pregnancy and 798 EVP miRNA were profiled in mature milk samples (collected approximately six weeks postpartum) using the NanoString nCounter platform. In covariate-adjusted models, AHEI-2010 was positively associated (Q < 0.05) with levels of miR-1283, miR-520h, and mir-570-3p in milk EVPs. Predicted target genes of these diet-associated miRNA are enriched in pathways related to lactation and mammary development (PI3 kinase signaling and Wnt signaling pathways) and milk protein and fat synthesis (PI3 kinase signaling). Further research is needed to investigate whether these diet-associated miRNA influence lactation, human milk quality, and child growth and development.

Helicobacter pylori (H. pylori) infection is a well-established risk factor for gastric adenocarcinoma, one of the leading causes of cancer-related death worldwide. While H. pylori infection induces significant DNA methylation changes, the cell type-specific epigenetic mechanisms contributing to carcinogenesis are not understood. To investigate these mechanisms, we analysed publicly available DNA methylation data from normal gastric mucosa of gastric cancer cases and controls stratified by H. pylori infection status, as well as tumour tissue from stomach adenocarcinoma. Using cell-type deconvolution and statistical modelling, we assessed epigenetic age acceleration, mitotic tick rate, cell-type composition, repetitive element methylation, and differentially methylated cell types. We reveal that (1) H. pylori infection is associated with increased epigenetic age acceleration and mitotic tick rate after adjustment for cell-type, independent of cancer status; (2) H. pylori infection corresponds to reduced epithelial and fibroblast proportions and increased infiltration of immune cell types, independent of cancer status; and (3) H. pylori infection influences LINE-1 and ERV repetitive element methylation in a cell type-specific fashion, particularly in epithelial and monocyte lineages. Our findings suggest that H. pylori infection induces lasting, cell-specific epigenetic alterations that may promote a pro-inflammatory and carcinogenic gastric microenvironment through altered cell pathways, genomic instability, and sustained inflammation.

DNA methylation, an epigenetic mark, has become a common outcome in epidemiological studies with the aid of affordable and reliable technologies. Yet the most widespread technique used to assess methylation, bisulfite conversion, does not allow for the differentiation of regular DNA methylation (5-mC) and other cytosine modifications, like that of hydroxymethylation (5-hmC). As both 5-mC and 5-hmC have distinct biological roles, sometimes with opposing effects, it is crucial to understand the difference between these marks. To characterize 5-mC and 5-hmC in cord blood and expand on previously published results in smaller cohorts, 73 samples from infants in the Michigan Mother Infant Pairs cohort were paired bisulfite and oxidative bisulfite converted. 5-mC and 5-hmC were assessed on the Illumina Infinium EPIC array, using maximum likelihood methods, and sex-specific differences of these marks were analyzed. 5-mC and 5-hmC were both broadly distributed across the genome, and 5-hmC was prevalent, with proportions of 0.01-0.55. Sex-specific analysis revealed total methylation was different on 17,000 sites (q<0.05), but only different at 1,866 and 5 sites of 5-mC and 5-hmC specifically. These results add additional support to the literature and demonstrate the importance of differentiating between 5-mC and 5-hmC in epidemiological studies going forward.