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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE158405 | GEO | 2020/11/24

REPOSITORIES: GEO

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

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 | GSE158404 | GEO

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

2020-11-24 | GSE137812 | GEO

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

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

| PRJNA665179 | ENA

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

Project description:De novo DNA methyltransferase activity in colorectal cancer is directed towards H3K36me3 marked CpG island

| PRJNA665164 | ENA

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

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

| PRJNA573110 | ENA

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

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

| PRJNA665180 | ENA

Comprehensive analysis of orphan CpG islands identifes novel promoters with conserved DNA methylation dynamics

Project description:We report the application of single molecule-based sequencing technology in combination with CXXC affinity purifcation (CAP-seq), MBD affinity purification (MAP-seq) and chromatin immunoprecipitation (ChIP-seq) to generate reciprocal methylation and chromatin modifcation maps in human and mouse. We find that contrary to sequence based prediction methods that humans and mice possess highly equivalent compliments of CpG islands (CGIs). The majority of these CGIs are positive for the active histone modification; H3K4me3 in embryonic stem cells (ES cells) the magnitude of which is correlated with the local density of non-methylated CpG. Approximately half of the human and mouse CGIs are distal to annotated gene promoters, yet more than 40% identify unanticipated transcription start sites as defined by RNA polymerase occupancy and published RNA mapping data. These orphans CGIs preferentially acquire DNA methylation in somatic cells, and this corresponds with a loss of H3K4me3 and RNA polymerase II at these sites. Conversely abnormal CGI methylation found in colorectal tumours showed a distinct distribution relative to that found in normal somatic tissues displaying preferential association with loci marked by H3K27me3 in human ES cells. This study provides a comprehensive functional assessment of CGIs in normal and diseased tissues. Examination of CGI methylation status in human and mouse primary tissues.

2010-10-04 | E-GEOD-21442 | biostudies-arrayexpress

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

Project description: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.

2019-06-18 | GSE111173 | GEO

Neuronal activation modulates enhancer activity of genes for excitatory synaptogenesis through de novo DNA methylation

Project description:Post-mitotic neurons exhibit DNA methylation changes, contrary to the longstanding belief that the epigenetic pattern in terminally differentiated cells is essentially unchanging. While the mechanism and physiological significance of DNA demethylation in neurons have been extensively elucidated, occurrence of de novo DNA methylation and its impacts have been much less investigated. Here we show that neuronal activation induces global de novo DNA methylation at enhancer regions that can repress target genes in primary cultured hippocampal neurons. The functional significance of this de novo DNA methylation was underpinned by the demonstration that inhibition of DNA methyltransferase (DNMT) activity decreased neuronal activity-induced excitatory synaptogenesis. Overexpression of WW and C2 Domain containing 1 (Wwc1), a representative target gene of de novo DNA methylation, could phenocopy this DNMT inhibition-induced decrease in the synaptogenesis. We found that both DNMT1 and DNMT3a were required for the neuronal activity-induced de novo DNA methylation of Wwc1 enhancer. Taking these findings altogether, we concluded that activity-induced de novo DNA methylation affecting gene expression has impacts on neuronal physiology comparable to those of DNA demethylation.

2020-04-26 | GSE149342 | GEO

A Primary Role of TET Proteins in Establishment and Maintenance of De Novo Bivalency at CpG Islands of Developmental Genes

Project description:TET protein-catalyzed 5mC oxidation not only creates novel DNA modifications such as 5hmC, but also initiates active or passive DNA demethylation. However, the TETsâ function in crosstalk with specific histone modifications is largely elusive. Here, we show that TET2-mediated DNA demethylation plays a primary role in the de novo establishment and maintenance of H3K4me3/H3K27me3 bivalent domain underlying the methylated DNA CpG islands (CGIs). Overexpression of wild type (WT) but not catalytic inactive mutant (Mut) TET2 in TET-low-expressing cells results in increase of 5hmC level and accompanying DNA demethylation at a subset of CGIs. Importantly, this is sufficient to create de novo bivalent domains at these loci. Genome-wide analysis reveals that these de novo synthesized bivalent domains are largely associated with a subset of key developmental gene promoters, which are often located within CpG islands that are previously hyper-methylated and silenced. On the other hand, depletion of Tet1 and Tet2 in mouse ES cells results in an apparent loss of H3K27me3 at bivalent domains, which are located within CGIs and associated with a particular set of key developmental gene promoters. Collectively, these data suggest that TET proteins have a primary role in charge of regulating the crosstalk between two key epigenetic mechanisms, DNA methylation and histone methylation (H3K4me3 and H3K27me3), particularly at a subset of CpG islands associated with developmental genes. We examined H3K4me3,H3K27me3,5mC and 5hmC in 293T and mES cell types,using Illumina Hiseq2500.

2016-07-25 | E-GEOD-72481 | biostudies-arrayexpress

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