Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

De novo DNA methylation at imprinted loci during reprogramming into naïve and primed pluripotency

ABSTRACT: CpG islands (CGIs) including those at imprinting control regions (ICRs) are protected from de novo methylation in somatic cells. However, many cancers often exhibit CGI hypermethylation, implying that the machinery is impaired in cancer cells. Here, we conducted a comprehensive analysis of CGI methylation during the somatic cell reprogramming. Although most CGIs remain hypomethylated, a small subset of CGIs, particularly at several ICRs, were often de novo methylated in reprogrammed pluripotent stem cells (PSCs). Such de novo ICR methylation was linked with the silencing of reprogramming factors, which occurs at a late stage of reprogramming. The ICR-preferred CGI hypermethylation was similarly observed in human PSCs. Mechanistically, ablation of Dnmt3a prevented PSCs from de novo ICR methylation. Notably, the ICR-preferred CGI hypermethylation was observed in pediatric cancers, while adult cancers exhibit genome-wide CGI hypermethylation. These results may have important implications in the pathogenesis of pediatric cancers and the application of PSCs.

ORGANISM(S): Mus musculus

PROVIDER: GSE111173 | GEO | 2019/06/18

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Engineering Pluripotent DNA Methylation by CpG Island Methylation Response (CIMR) to Synthetic CpG-free ssDNA Insertion

Project description:Integration of synthetic CpG Free DNA induces de novo DNAme in the flanking CpG island. Cellular differentiation requires global changes to DNA methylation (DNAme), where it functions to regulate transcription factor and chromatin remodeling activity, and genome interpretation. Here, we describe a simple DNAme engineering approach in pluripotent stem cells (PSCs), extending across large stretches of CpG dense “islands (CGIs).” Integration of synthetic CpG free single-stranded DNA (ssDNA) induces a target CpG Island Methylation Response (CIMR) in multiple PSC lines, Nt2d1 embryonal carcinoma cells, and mouse PSCs, but not in highly methylated CpG Island Methylator Phenotype (CIMP) positive cancer lines. CIMR DNAme at MLH1 spans the CGI, is robustly maintained throughout cellular differentiation, suppresses target gene activity, and sensitizes derived cardiomyocytes and thymic epithelial cells to the chemotherapy cisplatin. Additional CIMR DNAme is reported on at TP53 and ONECUT1 CGIs. Collectively, this new resource enables total CpG Island DNAme engineering in pluripotency and the genesis of novel epigenetic models of development and disease

2023-06-21 | GSE210680 | GEO

Smchd1 dependent and independent pathways determine developmental dynamics of CpG island methylation on the inactive X chromosome.

Project description:X chromosome inactivation involves multiple levels of chromatin modification, established progressively and in a stepwise manner during early development. The chromosomal protein Smchd1 has recently been shown to play an important role in DNA methylation of CpG islands (CGIs), a late step in the X inactivation pathway required for long-term stability of gene silencing. Here we show that inactive X chromosome (Xi) CGI methylation can occur via either Smchd1 dependent or independent pathways. Smchd1 dependent CGI methylation, the primary pathway, is acquired gradually over an extended period, whereas Smchd1 independent CGI methylation occurs rapidly after the onset of X inactivation. The de novo methyltransferase Dnmt3b is required for methylation of both classes of CGI, whereas Dnmt3a and Dnmt3L are dispensable. Xi CGIs methylated by these distinct pathways differ in respect to their sequence characteristics and immediate chromosomal environment. We discuss the implications of these results for understanding CGI methylation during development.

2012-10-15 | GSE37333 | GEO

Smchd1 dependent and independent pathways determine developmental dynamics of CpG island methylation on the inactive X chromosome.

2012-10-15 | E-GEOD-37333 | biostudies-arrayexpress

LTR retrotransposons transcribed in oocytes drive species-specific and heritable changes in DNA methylation

Project description:De novo DNA methylation (DNAme) occurs coincident with transcription during mouse oogenesis. As many oocyte transcripts originate in Long Terminal Repeats (LTRs), which are divergent across species, we examined whether polymorphic LTR-initiated transcription units (LITs) shape the oocyte methylome. We identified thousands of syntenic regions in mouse, rat and human, including CpG islands (CGIs), that show divergent DNAme associated with polymorphic LITs. Notably, many CGI promoters methylated exclusively in mouse and/or rat are embedded within rodent-specific LITs, and show persistent maternal methylation in the blastocyst. Polymorphic LITs are also responsible for divergent methylation of CGI promoters in distantly related mouse strains, revealing that LITs also promote intra-species diversification of promoter DNAme.

2018-07-06 | GSE112622 | GEO

Two competing mechanisms of DNMT3A recruitment regulate the dynamics of de novo DNA methylation at CpG islands

Project description:Precise deposition of CpG methylation is critical for mammalian development and tissue homeostasis and is often dysregulated in human diseases. The localization of de novo DNA methyltransferases 3A (DNMT3A) and 3B (DNMT3B) is facilitated by PWWP domain recognition of histone H3 lysine 36 (H3K36) methylation (Baubec et al. 2015, Weinberg et al. 2019) and is normally excluded from CpG islands (CGIs) (Wu et al. 2010). However, CpG methylation of CGIs that are regulated by Polycomb repressive complexes (PRCs) has been observed during embryogenesis (Chen et al. 2019), cellular differentiation (Mohn et al. 2008), and cancer progression (Ohm et al. 2007, Schlesinger et al. 2007, Widschwendter et al. 2007), suggesting that an uncharacterized mechanism exists to compete for de novo DNMT recruitment. Here we report that DNMT3A PWWP domain mutations recently identified in paragangliomas (Remacha et al. 2018) and microcephalic dwarfism (Heyn et al. 2019) promote localization of DNMT3A to CGIs in a PRC1-dependent manner. Genome-wide analysis shows that DNMT3A PWWP mutants redistribute to regions containing ubiquitylation of histone H2A at lysine 119 (H2AK119Ub) deposited by PRC1, irrespective of the levels of PRC2-catalyzed tri-methylation of histone H3 at lysine 27 (H3K27me3). DNMT3A, but not DNMT3B, is capable of directly interacting with H2AK119Ub-modified nucleosomes through a putative amino-terminal ubiquitin-dependent recruitment (UDR) region, which serves as an alternative form of genomic targeting in cells upon loss of PWWP reader function. Ablation of PRC1 abrogates localization of DNMT3A PWWP mutants to CGIs and prevents aberrant hypermethylation at these sites. Our study implies that a balance between DNMT3A recruitment by distinct reader domains guides de novo CpG methylation and may underlie the abnormal DNA methylation landscapes observed in human cancers and developmental disorders.

2021-05-13 | GSE147879 | GEO

BANP is an essential transcription factor that opens chromatin and activates CpG island regulated genes

Project description:While the majority of RNA polymerase II initiation events in mammalian genomes take place within CpG island (CGI) promoters, our understanding of their regulation remains limited. Here we combine single-molecule footprinting with interaction proteomics to identify BANP as a critical CGI regulator and the long sought-after TF that binds the orphan CGCG element in mouse and human. We show that BANP drives the activity of essential metabolic genes in the mouse genome in pluripotent and terminally differentiated cells. However, BANP binding is strongly repelled by DNA methylation of its motif in vitro and in vivo, which epigenetically restricts most binding to CGIs and accounts for its absence at aberrantly methylated CGIs in cancer cells. Upon binding to an unmethylated motif, BANP opens chromatin and phases nucleosomes. Our results establish Banp as a critical activator and put forth a model whereby CGI promoter activity relies on methylation-sensitive TFs capable of chromatin opening.

2021-06-16 | PXD024794 | Pride

De novo DNA methyltransferase activity in colorectal cancer is directed towards H3K36me3 marked CpG island (RRBS)

Project description:The aberrant gain of DNA methylation at CpG islands (CGIs) is frequently observed in colorectal tumours and may silence the expression of tumour suppressors such as MLH1. Current models propose that these CGIs are targeted by de novo DNA methyltransferases (DNMTs) in a sequence-specific manner but this has not been tested. Using ectopically integrated CGIs, we find that aberrantly methylated CGIs are subject to low levels of de novo DNMT activity in colorectal cancer cells. By delineating DNMT targets, we find that instead de novo DNMT activity is targeted primarily to CGIs marked by the histone modification H3K36me3, a mark associated with transcriptional elongation. These H3K36me3 marked CGIs are heavily methylated in colorectal tumours and the normal colon suggesting that de novo DNMT activity at CGIs in colorectal cancer is focused on similar targets to normal tissues and not greatly remodelled by tumourigenesis.

2020-11-24 | GSE137812 | GEO

De novo DNA methyltransferase activity in colorectal cancer is directed towards H3K36me3 marked CpG island (H3K36me3 ChIP-Rx_seq)

2020-11-24 | GSE158404 | GEO

De novo DNA methyltransferase activity in colorectal cancer is directed towards H3K36me3 marked CpG island (T7-DNMT3B ChIP-Rx_seq)

2020-11-24 | GSE158405 | GEO

Cancer-associated DNA Hypermethylation of Polycomb Targets Requires DNMT3A Dual Recognition of histone H2AK119 Ubiquitination and the Nucleosome Acidic Patch [EM-Seq]

Project description:During tumor development, promoter CpG islands (CGIs) that are normally silenced by Polycomb repressive complexes (PRCs) become DNA hypermethylated. The molecular mechanism by which de novo DNA methyltransferase(s) catalyze CpG methylation at PRC-regulated regions remains unclear. Here we report a cryo-EM structure of DNMT3A long isoform (DNMT3A1) N-terminal region in complex with nucleosome carrying PRC1-mediated histone H2A lysine 119 mono-ubiquitination (H2AK119Ub). We identify regions within the DNMT3A1 N-terminus that bind H2AK119Ub and the nucleosome acidic patch. This bidentate interaction is specifically required for effective DNMT3A1 engagement with H2AK119Ub-modified chromatin in cells. Furthermore, aberrant redistribution of DNMT3A1 to Polycomb target genes inhibits their transcriptional derepression during cell differentiation and recapitulates the cancer-associated DNA hypermethylation signature, an effect rescued by disruption of DNMT3A1-acidic patch interaction. Together, our analyses reveal a binding interface critical for countering promoter CGI DNA hypermethylation, a major molecular hallmark of cancer.

2024-08-31 | GSE247018 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data