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DNMT1-associated long non-coding RNA regulate global gene expression and DNA methylation in colon cancer

ABSTRACT: The investigation of the association of long non-coding RNAs (lncRNAs) with DNMT1 by RIP-seq reveals that DNMT1 interacts with DACOR1. We identified the genomic occupancy sites of DACOR1 through ChIRP-seq, which we found to significantly overlap with known differentially methylated regions (DMRs) in colon tumors. Induction of DACOR1 in colon cancer cell lines significantly reduced their ability to form colonies in vitro, suggesting a growth suppressor function. Consistent with the observed phenotype, induction of DACOR1 led to the activation of tumor-suppressor pathways and attenuation of cancer-associated metabolic pathways. Notably, DACOR1 induction resulted in down-regulation of Cystathionine β-synthase (CBS), which is known to lead to increased levels of S-adenosyl methionine (SAM) – the key methyl donor for DNA methylation.

ORGANISM(S): Homo sapiens

PROVIDER: GSE58989 | GEO | 2015/09/15

SECONDARY ACCESSION(S): PRJNA254057

REPOSITORIES: GEO

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DNMT1-associated long non-coding RNA regulate global gene expression and DNA methylation in colon cancer

Project description:The investigation of the association of long non-coding RNAs (lncRNAs) with DNMT1 by RIP-seq reveals that DNMT1 interacts with DACOR1. We identified the genomic occupancy sites of DACOR1 through ChIRP-seq, which we found to significantly overlap with known differentially methylated regions (DMRs) in colon tumors. Induction of DACOR1 in colon cancer cell lines significantly reduced their ability to form colonies in vitro, suggesting a growth suppressor function. Consistent with the observed phenotype, induction of DACOR1 led to the activation of tumor-suppressor pathways and attenuation of cancer-associated metabolic pathways. Notably, DACOR1 induction resulted in down-regulation of Cystathionine ?-synthase (CBS), which is known to lead to increased levels of S-adenosyl methionine (SAM) – the key methyl donor for DNA methylation. The DNA methyltransferase DNMT1 was immunoprecipitated and all associated RNAs were identified by RNA-seq and subsequent bioinformatic analyses. Samples were prepared for DNA sequencing through the ChIRP-seq protocol which uses antisense DNA oligos to bind to DACOR1 and pull down associated DNA in complex. We sequenced one sample with DACOR1 specific probes and non-specific DNA probes as control. Three samples were collected for each control lentivirus transduced V852 colon cancer line and DACOR1 lentivirus transduced V852. Samples were processed for RNA-sequencing and analyzed through differential expression analysis.

2015-09-15 | E-GEOD-58989 | biostudies-arrayexpress

satmut_utils: a simulation and variant calling package for multiplexed assays of variant effect

Project description:We use stable expression of a cystathionine-beta synthase (CBS) variant library in HEK293T cells to identify CBS coding sequence variants that alter mRNA abundance

2022-04-22 | GSE201057 | GEO

Expression data from mouse CD4+ T cells

2015-07-22 | GSE59241 | GEO

Expression data from mouse CD4+ T cells

Project description:Hydrogen sulfide (H2S) is an endogenous gasotransmitter and is capable of regulating various endogenous signaling pathways, inculding inflamation and immune response. In mammals, H2S is mainly generated by two pyridoxal-5’-phosphate-dependent enzymes, termed cystathionine beta-synthase (CBS) and cystathionine gamma-lyase (CSE). CBS-deficient mice showed autoimmune disorders. H2S play important roles in T cell development and differentiation, especially Treg cells development and differentiation. We used microarrays to detail the global gene expression of WT and CBS-deficient CD4+ T cells. CD4+ T cells from WT and CBS-deficient mice were isolated for RNA extraction and hybridization on Affymetrix microarrays. We sought to obtain the homogeneous populations of mice at 6 weeks in order to increase the temporal resolution of expression profiles.

2015-07-22 | E-GEOD-59241 | biostudies-arrayexpress

A mutant DNMT1 enhances tumorigenicity with focal hypermethylation and global hypomethylation

Project description:Site-specific hypermethylation of tumor suppressor genes accompanied by genome-wide hypomethylation are epigenetic hallmarks of malignancy. However, molecular mechanisms that drive these linked changes in DNA methylation remain obscure. DNA methyltransferase 1 (DNMT1), the principle enzyme responsible for maintaining methylation patterns is commonly dysregulated in tumors. Replication foci targeting sequence (RFTS) is an N-terminal domain of DNMT1 that inhibits DNA-binding and catalytic activity, suggesting that RFTS deletion would result in gain of DNMT1 function. However, earlier data suggested that RFTS is required for DNMT1 activity. Here, we determined cellular consequences of RFTS deletion from DNMT1 in immortalized human bronchial epithelial cells. Compared to full-length DNMT1, ectopic expression of DNMT1- ?RFTS caused greater malignant transformation and enhanced promoter methylation that silenced DAPK and DUOX1 gene expression and increased intensity of promoter methylation across the genome. Strikingly, DNMT1-?RFTS also produced genomic hypomethylation and demethylation of Satellite 2 repeat sequences. Because deletion of RFTS is sufficient to induce focal hypermethylation and global hypomethylation in parallel, evidence suggests that the RFTS domain is a target responsible for epigenetic changes in cancer. DNA samples from HBEC3 cells transfected with vector control and HBEC3 cells with full-length and RFTS-deleted DNMT1 were assessed for genome-wide methylation using the microarray-based high resolution HpaII tiny fragment enriched by ligation-mediated PCR (HELP) assay.

2014-09-30 | E-GEOD-57829 | biostudies-arrayexpress

RIPSEQ DNMT1 HL60

Project description:Identification of the all RNA species associated with DNMT1. Using a comparative genome-scale approach we identified and correlated the RNA species physically associated with DNMT1 and proximal to the annotated genes to the methylation status of the corresponding loci and expression levels of the respective genes. This comparative approach delineated the first -DNMT1 centered- 'epitranscriptome' map, a comprehensive map cross-referencing DNMT1-interacting transcripts to (i) DNA methylation and (ii) gene expression profile. Relationship between DNMT1-RNA interactions, DNA methylation and gene expression

2012-12-01 | E-GEOD-32162 | biostudies-arrayexpress

RFTS-deleted DNMT1 enhances tumorigenicity with focal hypermethylation and global hypomethylation

Project description:Site-specific hypermethylation of tumor suppressor genes accompanied by genome-wide hypomethylation are epigenetic hallmarks of malignancy. However, molecular mechanisms that drive these linked changes in DNA methylation remain obscure. DNA methyltransferase 1 (DNMT1), the principle enzyme responsible for maintaining methylation patterns is commonly dysregulated in tumors. Replication foci targeting sequence (RFTS) is an N-terminal domain of DNMT1 that inhibits DNA-binding and catalytic activity, suggesting that RFTS deletion would result in gain of DNMT1 function. However, earlier data suggested that RFTS is required for DNMT1 activity. Here, we determined cellular consequences of RFTS deletion from DNMT1 in immortalized human bronchial epithelial cells. Compared to full-length DNMT1, ectopic expression of DNMT1- ΔRFTS caused greater malignant transformation and enhanced promoter methylation that silenced DAPK and DUOX1 gene expression and increased intensity of promoter methylation across the genome. Strikingly, DNMT1-ΔRFTS also produced genomic hypomethylation and demethylation of Satellite 2 repeat sequences. Because deletion of RFTS is sufficient to induce focal hypermethylation and global hypomethylation in parallel, evidence suggests that the RFTS domain is a target responsible for epigenetic changes in cancer.

2014-09-30 | GSE57829 | GEO

ATM mediates pRB function to control DNMT1 protein stability and DNA methylation

Project description:The retinoblastoma tumor suppressor gene (RB) product has been implicated in epigenetic control of gene expression owing to its ability to physically bind to many of chromatin modifiers. However, the biological and clinical significance of this activity was not well elucidated. To address this, we performed genetic and epigenetic analyses in an Rb-deficient mouse thyroid C cell tumor model. Here we report that the genetic interaction of Rb and ATM regulates DNMT1 protein stability, and hence controls the DNA methylation status in the promoter of at least Ink4a, Shc2, FoxO6 and Noggin genes. Further, we demonstrate that inactivation of pRB promotes the Tip60 (acetyltransferase)-dependent ATM activation, allows activated ATM to physically bind to DNMT1 forming a complex with Tip60 and UHRF1 (E3 ligase), and consequently accelerates DNMT1 ubiquitination driven by Tip60-dependent acetylation. Our results indicate that inactivation of pRB pathway in coordination with aberration in DNA damage response leads to abnormal DNA methylation pattern by affecting the stability of DNMT1. 163; Rb-/-;ATM-/- MEFs, D4; DNMT1 knockdown from 163 cells and analysed at day 4, WT8S; 163 cells reconstituted with ATM expression vector

2013-05-31 | E-GEOD-47501 | biostudies-arrayexpress

Distinct catalytic-dependent or -independent activities of DNMT1 in mouse embryonic stem cells

Project description:DNMT1 maintains DNA methylation profile and regulates gene expression. Although DNMT1 interacts with other proteins that regulate gene expressions, it remains unclear how the protein-protein interaction or the catalytic activity of DNMT1 itself affect gene expression and DNA methylation pattern. In this study, immunofluorescence staining showed abnormal DNA methylation pattern in chromosome arms of DNMT1-deficient (1KO) mouse embryonic stem cells (ESCs), and we hypothesized that DNMT1 helps methylation activity of DNMT3. To validate this hypothesis, we generate transgenic 1KO ESCs expressing catalytic inactive DNMT1 (1KO+1CI). Here, we used RNA-seq to analyze the effect of catalytic-dependent or -independent DNMT1 activity on gene expression in ESCs or epiblast-like cells (EpiLCs) induction.

2022-01-01 | GSE179006 | GEO

Cystathionine beta synthase (CBS) Over expression vs PLenti6 Expression Vector Human Bronchial Epithelial Cells (HBEC)

Project description:Cystathionine Beta Synthase (CBS), an enzyme that utilizes a methionine precursor to generate glutathione (GSSH), has been implicated in the mitigation of ROS production in COPD lung. Additionally, post-translational modification analysis on mouse and human cells treated with cigarette smoke showed the unique presence of mono- and di-methylated histone H3 lysine 27 that was not seen in controls, suggesting that cigarette smoke could lead to loss of Polycomb Repressive Complex 2 (PRC2) activity. To elucidate CBS as a potential upstream target for PRC2 inhibition, we overexpressed CBS in Human Bronchial Epithelial Cells (HBECs), grew them as 2D cultures, then conducted bulk RNA seq analysis.

2022-06-30 | GSE183858 | GEO

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