Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

A role of Polycomb in the maintenance of hypomethylation for DNA methylation valley

ABSTRACT: DNA methylation valleys (DMVs) are large loci that are devoid of DNA methylation in the genome. We show that DMVs are hypomethylated at most stages in development and are highly conserved across vertebrates. Importantly, DMVs are hotspots of regulatory regions for key developmental regulator genes. 4C-seq analyses indicate that DMVs are insulated and self-interacting domains. By analyzing a panel of DNA methylomes for the mouse tissues, we have identified a subset of DMVs that are dynamically methylated. These DMVs are strongly enriched by Polycomb and their histone substrate H3K27me3 when the associated genes are silenced, and surprisingly show elevated DNA methylation upon gene activation. In support of a role of Polycomb in DMV hypomethylation, we observed aberrant methylation in DMVs in mESCs deficient for Eed. Finally, we showed that Polycomb regulates hypomethylation of DMVs likely through TET proteins.

ORGANISM(S): Mus musculus

PROVIDER: GSE102753 | GEO | 2017/12/24

SECONDARY ACCESSION(S): PRJNA398611

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

Poised RNA polymerase II co-localises with Polycomb repression at multi-lineage developmental regulator genes in differentiated neurons

Project description:Polycomb repression is tightly associated with promoter co-occupancy of poised RNA polymerase II (RNAPII) in mouse Embryonic Stem Cells (ESCs). However, it remains unclear whether poising is a specific feature of ESCs or also associated with Polycomb during cell differentiation. Here, we show that RNAPII poising at Polycomb repressed genes is found in five stages of ESC differentiation to dopaminergic neurons. We find that key transcription factor genes of non-neuronal lineages are kept silent in the neuronal lineage through Polycomb repression in co-association with poised RNAPII in the absence of DNA methylation within DNA Methylation Valleys (DMVs). This group of poised transcription factors are preferential candidate master regulators for trans-differentiation of neurons into different lineages. We conclude that RNAPII poising is a general feature of Polycomb repression and cell plasticity in pluripotent stem cells and terminally differentiated neurons.

2017-09-29 | GSE94364 | GEO

Developmental Pathways Are Epigenetically Reprogrammed during Lung Cancer Brain Metastasis

Project description:Non-small cell lung cancer (NSCLC) is one of the most commonly diagnosed and deadliest cancers worldwide, owing in large part to roughly half of all patients initially presenting with both primary and metastatic disease. While the major events in the metastatic cascade have been identified, a mechanistic understanding of how NSCLC routinely, successfully colonizes the brain is largely unknown. Recent studies have begun demonstrating the role of epigenetic mis-regulation within tumorigenesis as well as in the metastatic process, including widespread changes in DNA methylation and histone modifications. To better understand the role of DNA methylation alterations in NSCLC metastasis to brain, we measured DNA methylation during disease progression for 12 patients, globally profiling the methylation of their normal lung, primary lung tumor, and brain metastasis. We found that the variation in methylation is just as great; albeit less coordinated across genomic features, during metastatic spread as compared to primary tumorigenesis. The greatest recurrent methylation changes during metastatic progression occurred over DNA methylation valleys (DMVs) harboring H3K9me3 as well as bivalent marks H3K27me3 and H3K4me1 enrichment in normal lung. Mapping EZH2, the catalytic subunit of polycomb repressive complex 2 (PCR2), binding locations in H1299, a lymph node-derived lung cancer cell line, revealed a loss of EZH2 binding within DMVs accompanied by an increase in DNA methylation, exemplifying epigenetic switching. The vast majority of these differentially methylated region-associated DMVs harbor developmental genes, suggesting that altered epigenetic regulation of developmentally important genes may confer a selective advantage during metastatic progression.

2022-07-01 | GSE203216 | GEO

Phosphatidic acid features double membrane vesicle formation during Hepatitis C and SARS-CoV-2 infection

Project description:Double membrane vesicles (DMVs) are used as replication organelles by pathogenic RNA viruses such as hepatitis C virus (HCV) and severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Viral DMVs are morphologically analogous to DMVs formed during autophagy, and although the proteins required for DMV formation are extensively studied, the lipids driving their biogenesis are largely unknown. Here we show that production of the lipid phosphatidic acid (PA) by acylglycerolphosphate acyltransferase (AGPAT) 1 and 2 in the ER is important for DMV biogenesis in autophagy and viral replication. Using DMVs in HCV-replicating cells as model, we found that AGPATs are recruited to and critically contribute to viral replication in HCV and SARS-CoV-2 infected cells. AGPAT1/2 double knockout impaired HCV and SARS-CoV-2 induced DMV biogenesis as well as formation of autophagosomes. By using correlative light and electron microscopy, we observed the relocalisation of AGPAT proteins to viral DMVs. In addition, an intracellular PA sensor accumulated at DMV formation sites, consistent with elevated levels of PA in fractions of purified DMVs analyzed by lipidomics. Apart from AGPATs, PA is generated by alternative pathways via phosphotidylcholine (PC) and diacylglycerol (DAG). Pharmacological inhibition of these synthesis pathways also impaired HCV and SARS-CoV-2 replication. These data identify PA as an important lipid that is used in seemingly disparate biological processes, i.e. autophagy and replication organelle formation by diverse RNA viruses. In addition, our data argue that host-targeting therapy aiming at PA synthesis pathways might be suitable to control SARS-CoV-2 replication.

2022-01-24 | PXD029692 | Pride

5-hydroxymethylcytosine (5hmC) profiling of H1 WT hESCs

Project description:DNA methylation is essential to mammalian development, and aberrant regulation can lead to disease. The enzymes responsible for deposition and removal of DNA methylation have been identified, but how tightly regulated DNA methylation patterns are achieved globally remains a central question. To discover regulators of DNA methylation in human Embryonic Stem Cells (hESCs), we engineered a DNA methylation reporter line and performed a genome-wide CRISPR/Cas screen. Through our screen, we identified the functionally uncharacterized gene QSER1, which proved to be essential for protection from DNA hypermethylation at bivalent promoters and poised enhancers of developmental genes, especially those residing in DNA Methylation Valleys (DMVs). Further mechanistic enquiry revealed that QSER1 protein depends on TET1 for efficient recruitment to DNA, and QSER1 occupancy inhibits the binding of DNMT3B. Our discovery of QSER1 is a major advance in understanding TET-dependent protection from DNA hypermethylation and provides mechanistic insight into how epigenetic factors can cooperate to target locus-specific regulation.

2021-03-19 | GSE150015 | GEO

DNA hypomethylation bypasses the interploidy hybridization barrier in Arabidopsis

Project description:Plants of different ploidy levels are separated by a strong postzygotic hybridization barrier that is established in the endosperm. Deregulated parent-of-origin specific genes are causal for the response to interploidy hybridizations, revealing an epigenetic basis of this phenomenon. In this study we present evidence that paternal hypomethylation can bypass the interploidy hybridization barrier by alleviating the requirement of the epigenetic Polycomb Repressive Complex 2 (PRC2) in the endosperm. Bypass of the barrier is mediated by suppressed expression of imprinted genes. We show that hypomethylated pollen causes redistribution of CHG methylation to PRC2 target genes, revealing that different epigenetic modifications can functionally substitute for each other. Our work presents a method and the underlying mechanism for the generation of viable triploids, providing an impressive example for the potential of epigenome manipulations for plant breeding. Examination of DNA methylation in Arabidopsis endosperm, embryo, and pollen, and gene expression in seeds

2014-09-22 | E-GEOD-53642 | biostudies-arrayexpress

Gain of function DNMT3A mutations cause microcephalic dwarfism and hypermethylation of Polycomb-regulated regions (mouse RRBS)

Project description:DNA methylation and Polycomb are key factors in the establishment of vertebrate cellular identity and fate. Here we report de novo missense mutations in DNMT3A, encoding the DNA methyltransferase DNMT3A, that cause microcephalic dwarfism, a hypocellular disorder of extreme global growth failure. Substitutions in the PWWP domain abrogate binding to the histone modifications H3K36me2/3, and alter DNA methylation in patient cells. Polycomb-associated DNA methylation canyons/valleys, hypomethylated domains encompassing developmental genes, become methylated with concomitant depletion of H3K27me3 and H3K4me3 bivalent marks. Such de novo DNA methylation occurs during differentiation of Dnmt3aW326R pluripotent cells in vitro, and is also evident in Dnmt3aW326R/+ dwarf mice. We therefore propose that the interaction of the DNMT3A PWWP domain with H3K36me2/3 normally limits DNA methylation of polycomb-marked regions. Our findings implicate the interplay between DNA methylation and polycomb at key developmental regulators as a determinant of organism size in mammals.

2018-11-26 | GSE120557 | GEO

Gain of function DNMT3A mutations cause microcephalic dwarfism and hypermethylation of Polycomb-regulated regions (mouse NPC RNAseq)

2018-11-26 | GSE120555 | GEO

Gain of function DNMT3A mutations cause microcephalic dwarfism and hypermethylation of Polycomb-regulated regions (human RRBS)

2018-11-26 | GSE120554 | GEO

Gain of function DNMT3A mutations cause microcephalic dwarfism and hypermethylation of Polycomb-regulated regions (human fibroblast RNAseq)

2018-11-26 | GSE120553 | GEO

Gain of function DNMT3A mutations cause microcephalic dwarfism and hypermethylation of Polycomb-regulated regions (human fibroblast ChIP-seq)

2018-11-26 | GSE120551 | GEO