DNA methylation, its mediators and genome integrity.
Ontology highlight
ABSTRACT:
SUBMITTER: Meng H
PROVIDER: S-EPMC4400391 | biostudies-literature | 2015
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:Cells encounter a multitude of external and internal stress-causing agents that can ultimately lead to DNA damage, mutations and disease. A cascade of signaling events counters these challenges to DNA, which is termed as the DNA damage response (DDR). The DDR preserves genome integrity by engaging appropriate repair pathways, while also coordinating cell cycle and/or apoptotic responses. Although many of the protein components in the DDR are identified, how chemical modifications to DNA impact the DDR is poorly understood. This review focuses on our current understanding of DNA methylation in maintaining genome integrity in mammalian cells. DNA methylation is a reversible epigenetic mark, which has been implicated in DNA damage signaling, repair and replication. Sites of DNA methylation can trigger mutations, which are drivers of human diseases including cancer. Indeed, alterations in DNA methylation are associated with increased susceptibility to tumorigenesis but whether this occurs through effects on the DDR, transcriptional responses or both is not entirely clear. Here, we also highlight epigenetic drugs currently in use as therapeutics that target DNA methylation pathways and discuss their effects in the context of the DDR. Finally, we pose unanswered questions regarding the interplay between DNA methylation, transcription and the DDR, positing the potential coordinated efforts of these pathways in genome integrity. While the impact of DNA methylation on gene regulation is widely understood, how this modification contributes to genome instability and mutations, either directly or indirectly, and the potential therapeutic opportunities in targeting DNA methylation pathways in cancer remain active areas of investigation.
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Project description:The decompaction and re-establishment of chromatin organization immediately after mitosis is essential for genome regulation. Mechanisms underlying chromatin structure control in daughter cells are not fully understood. Here we show that a chromatin compaction threshold in cells exiting mitosis ensures genome integrity by limiting replication licensing in G1 phase. Upon mitotic exit, chromatin relaxation is controlled by SET8-dependent methylation of histone H4 on lysine 20. In the absence of either SET8 or H4K20 residue, substantial genome-wide chromatin decompaction occurs allowing excessive loading of the origin recognition complex (ORC) in the daughter cells. ORC overloading stimulates aberrant recruitment of the MCM2-7 complex that promotes single-stranded DNA formation and DNA damage. Restoring chromatin compaction restrains excess replication licensing and loss of genome integrity. Our findings identify a cell cycle-specific mechanism whereby fine-tuned chromatin relaxation suppresses excessive detrimental replication licensing and maintains genome integrity at the cellular transition from mitosis to G1 phase.
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Project description:Mouse embryos acquire global DNA methylation of their genome during implantation. However the exact roles of DNA methyltransferases (DNMTs) in embryos have not been studied comprehensively. Here we systematically analyze the consequences of genetic inactivation of Dnmt1, Dnmt3a and Dnmt3b on the methylome and transcriptome of mouse embryos. We find a strict division of function between DNMT1, responsible for maintenance methylation, and DNMT3A/B, solely responsible for methylation acquisition in development. By analyzing severely hypomethylated embryos, we uncover multiple functions of DNA methylation that is used as a mechanism of repression for a panel of genes including not only imprinted and germline genes, but also lineage-committed genes and 2-cell genes. DNA methylation also suppresses multiple retrotransposons and illegitimate transcripts from cryptic promoters in transposons and gene bodies. Our work provides a thorough analysis of the roles of DNA methyltransferases and the importance of DNA methylation for transcriptome integrity in mammalian embryos.
| S-EPMC7305168 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below.
2021-09-21 | GSE158011 | GEO
Project description:Major questions of neurological and psychiatric mechanisms involve the brain functions on a molecular level and cannot be easily addressed due to limitations in access to tissue samples. Post mortem studies are able to partly bridge the gap between brain tissue research retrieved from animal trials and the information derived from peripheral analysis (e.g., measurements in blood cells) in patients. Here, we wanted to know how fast DNA degradation is progressing under controlled conditions in order to define thresholds for tissue quality to be used in respective trials. Our focus was on the applicability of partly degraded samples for bisulfite sequencing and the determination of simple means to define cut-off values. After opening the brain cavity, we kept two consecutive pig skulls at ambient temperature (19-21°C) and removed cortex tissue up to a post mortem interval (PMI) of 120 h. We calculated the percentage of degradation on DNA gel electrophoresis of brain DNA to estimate quality and relate this estimation spectrum to the quality of human post mortem control samples. Functional DNA quality was investigated by bisulfite sequencing of two functionally relevant genes for either the serotonin receptor 5 (SLC6A4) or aldehyde dehydrogenase 2 (ALDH2). Testing our approach in a heterogeneous collective of human blood and brain samples, we demonstrate integrity of measurement quality below the threshold of 72 h PMI. While sequencing technically worked for all timepoints irrespective of conceivable DNA degradation, there is a good correlation between variance of methylation to degradation levels documented in the gel (R (2) = 0.4311, p = 0.0392) for advancing post mortem intervals (PMI). This otherwise elusive phenomenon is an important prerequisite for the interpretation and evaluation of samples prior to in-depth processing via an affordable and easy assay to estimate identical sample quality and thereby comparable methylation measurements.
| S-EPMC4435253 | biostudies-literature
Project description:BackgroundAccumulating evidence suggests that posttraumatic stress disorder (PTSD) may accelerate cellular aging and lead to premature morbidity and neurocognitive decline.MethodsThis study evaluated associations between PTSD and DNA methylation (DNAm) age using recently developed algorithms of cellular age by Horvath (2013) and Hannum et al. (2013). These estimates reflect accelerated aging when they exceed chronological age. We also examined if accelerated cellular age manifested in degraded neural integrity, indexed via diffusion tensor imaging.ResultsAmong 281 male and female veterans of the conflicts in Iraq and Afghanistan, DNAm age was strongly related to chronological age (rs ∼.88). Lifetime PTSD severity was associated with Hannum DNAm age estimates residualized for chronological age (β=.13, p=.032). Advanced DNAm age was associated with reduced integrity in the genu of the corpus callosum (β=-.17, p=.009) and indirectly linked to poorer working memory performance via this region (indirect β=-.05, p=.029). Horvath DNAm age estimates were not associated with PTSD or neural integrity.ConclusionsResults provide novel support for PTSD-related accelerated aging in DNAm and extend the evidence base of known DNAm age correlates to the domains of neural integrity and cognition.
| S-EPMC4695261 | biostudies-literature
Project description:DNA replication timing and 3D chromatin organisation are associated with epigenomic changes across large domains during human differentiation and cancer progression. However, it is unclear if epigenome changes, in particular cancer-associated DNA hypomethylation, is a consequence or cause of changes observed in higher order genome architecture. Here, we compare replication timing profiles and three dimensional (3D) genome organisation, using Hi-C and single cell Repli-Seq in the DNMT1 and DNMT3B DNA methyltransferases double knockout hypomethylated DKO1 colorectal cancer cell line and its parental HCT116 cell line. We find that the hypomethylated cells show a profound loss of replication timing precision, gain of single cell replication timing heterogeneity and loss of chromatin conformation integrity. Discrete regions, that undergo a large change in replication timing in the hypomethylated cells, are associated with a loss of allelic replication timing and shrinking of late replicating Partially Methylated Domain (PMD) boundaries. In contrast, conservation of replication timing after DNA methylation depletion at PMDs is associated with the formation of new H3K9me3/H3K4me3 bivalent domains which may serve to prevent ectopic transcription and maintain cell viability. Together our results show that a loss of global methylation, a common hallmark of cancer, directly impacts on the precision of replication timing and contribute to deregulation of the 3D chromatin architecture.
2021-09-21 | GSE158010 | GEO
Project description:DNA replication timing and 3D chromatin organisation are associated with epigenomic changes across large domains during human differentiation and cancer progression. However, it is unclear if epigenome changes, in particular cancer-associated DNA hypomethylation, is a consequence or cause of changes observed in higher order genome architecture. Here, we compare replication timing profiles and three dimensional (3D) genome organisation, using Hi-C and single cell Repli-Seq in the DNMT1 and DNMT3B DNA methyltransferases double knockout hypomethylated DKO1 colorectal cancer cell line and its parental HCT116 cell line. We find that the hypomethylated cells show a profound loss of replication timing precision, gain of single cell replication timing heterogeneity and loss of chromatin conformation integrity. Discrete regions, that undergo a large change in replication timing in the hypomethylated cells, are associated with a loss of allelic replication timing and shrinking of late replicating Partially Methylated Domain (PMD) boundaries. In contrast, conservation of replication timing after DNA methylation depletion at PMDs is associated with the formation of new H3K9me3/H3K4me3 bivalent domains which may serve to prevent ectopic transcription and maintain cell viability. Together our results show that a loss of global methylation, a common hallmark of cancer, directly impacts on the precision of replication timing and contribute to deregulation of the 3D chromatin architecture.
2021-09-21 | GSE159663 | GEO
Project description:Methylation of CpG dinucleotides is a fundamental mechanism of epigenetic regulation in eukaryotic genomes. Development of methods for rapid genome wide methylation profiling will greatly facilitate both hypothesis and discovery driven research in the field of epigenetics. In this regard, a single molecule approach to methylation profiling offers several unique advantages that include elimination of chemical DNA modification steps and PCR amplification.A single molecule approach is presented for the discernment of methylation profiles, based on optical mapping. We report results from a series of pilot studies demonstrating the capabilities of optical mapping as a platform for methylation profiling of whole genomes. Optical mapping was used to discern the methylation profile from both an engineered and wild type Escherichia coli. Furthermore, the methylation status of selected loci within the genome of human embryonic stem cells was profiled using optical mapping.The optical mapping platform effectively detects DNA methylation patterns. Due to single molecule detection, optical mapping offers significant advantages over other technologies. This advantage stems from obviation of DNA modification steps, such as bisulfite treatment, and the ability of the platform to assay repeat dense regions within mammalian genomes inaccessible to techniques using array-hybridization technologies.
| S-EPMC2516518 | biostudies-other
Project description:DNA methylation plays critical roles in gene regulation and cellular specification without altering DNA sequences. The wide application of reduced representation bisulfite sequencing (RRBS) and whole genome bisulfite sequencing (bis-seq) opens the door to study DNA methylation at single CpG site resolution. One challenging question is how best to test for significant methylation differences between groups of biological samples in order to minimize false positive findings.We present a statistical analysis package, methylSig, to analyse genome-wide methylation differences between samples from different treatments or disease groups. MethylSig takes into account both read coverage and biological variation by utilizing a beta-binomial approach across biological samples for a CpG site or region, and identifies relevant differences in CpG methylation. It can also incorporate local information to improve group methylation level and/or variance estimation for experiments with small sample size. A permutation study based on data from enhanced RRBS samples shows that methylSig maintains a well-calibrated type-I error when the number of samples is three or more per group. Our simulations show that methylSig has higher sensitivity compared with several alternative methods. The use of methylSig is illustrated with a comparison of different subtypes of acute leukemia and normal bone marrow samples.methylSig is available as an R package at http://sartorlab.ccmb.med.umich.edu/software.Supplementary data are available at Bioinformatics online.
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