Effect of epigenotoxic chemicals on transcriptomic profiles of human induced pluripotent stem cells [RNA-seq]
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE180452 | GEO | 2021/07/23
REPOSITORIES: GEO
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Project description:We studied the effects of chemical exposure on global DNA methylation by using mCherry-methyl-CpG-binding domain (MBD)-nls human induced pluripotent stem cells (iPSCs). According to the fluorescent MBD parameters, we divided the effects of 135 chemical on global DNA methylation into 3 categories; reduction (hypomethylation), increase (hypermethylation) and little/no effect. We performed DNA methylome assay to examine the effects of 6 epigenotoxic chemicals on genome-wide DNA methylation patterns in human iPSCs. Our results indicated that hypermethylation agents increased DNA methylation and downregulated the expression of genes involved in cell cycle or development.
2021-07-23 | GSE180453 | GEO
Project description:We studied the effects of chemical exposure on global DNA methylation by using mCherry-MBD-nls human iPS cells. By using 135 chemical library, we could devide the effects of global DNA methylation into 3 categories; reduction (hypomethylation), increase (hypermethylation) and little/no effect. We further performed both genome-wide DNA methylation and stemness-related gene expression (100 genes) analyses, and results indicated that hypermethylation agents increased DNA methylation and downregulated the expression of genes involved in cell cycle or development.
2023-04-01 | GSE228658 | GEO
Project description:DNA (cytosine-5) methyltransferase 1 (DNMT1) is essential for mammalian development and maintenance of DNA methylation following DNA replication in cells. The DNA methylation process generates S-adenosyl-L-homocysteine, a strong inhibitor of DNMT1. Here we report that S-adenosylhomocysteine hydrolase (SAHH/AHCY), the only mammalian enzyme capable of hydrolyzing S-adenosyl-L-homocysteine binds to DNMT1 during DNA replication. SAHH activates DNMT1 in vitro and its overexpression in mammalian cells leads to hypermethylation of the genome, whereas its inhibition by adenosine periodate resulted in hypomethylation of the genome. Hypermethylation was consistent in both gene bodies and repetitive DNA elements leading to both down- and up-regulation of genes. Similarly, hypomethylation led to both up- and down-regulation of genes suggesting methylated regions influence gene expression either positively or negatively. Cells overexpressing SAHH specifically up-regulated metabolic pathway genes and down-regulated PPAR and MAPK signaling pathways genes. Therefore, we suggest that alteration of SAHH level in the cell leads to aberrant DNA methylation, altered metabolite levels and gene expression.
2018-06-06 | PXD006476 | Pride
Project description:Cancer is characterised by DNA hypermethylation and gene silencing of CpG island-associated promoters, including tumour suppressor genes The methyl-CpG-binding domain (MBD) family of proteins bind to methylated DNA and can aid in the meditation of gene silencing by interaction with histone deacetylases and histone methyltransferases. However the mechanisms responsible for eliciting CpG island hypermethylation in cancer, and the potential role that MBD may proteins play in modulation of the methylome remain unclear. Our previous work demonstrated that MBD2 preferentially binds to the hypermethylated GSTP1 promoter CpG island in prostate cancer cells. Here, we use functional genetic approaches to investigate if MBD2 plays an active role in promoting DNA methylation. First, we show that loss of MBD2 results in inhibition of both maintenance and spread of de novo methylation of a transfected construct containing the GSTP1 promoter CpG island in prostate cancer cells and Mbd2-/- mouse fibroblasts. De novo methylation was rescued by transient expression of Mbd2 in Mbd2-/- cells. Second, we show that MBD2 depletion triggers significant hypomethylation genome-wide in prostate cancer cells with concomitant loss of MBD2 binding at promoter and enhancer regulatory regions. Finally, CpG islands and shores that become hypomethylated after MBD2 depletion in LNCaP cancer cells show significant hypermethylation in clinical prostate cancer, highlighting a potential active role of MBD2 in promoting cancer specific hypermethylation. Importantly, co-immunoprecipiation of MBD2 reveals that MBD2 associates with DNA methyltransferase (DNMT) enzymes 1 and 3A. Together our results demonstrate that MBD2 plays a critical role in â??rewritingâ?? the cancer methylome at specific regulatory regions. LNCaP prostate cancer cell line clones with reduced MBD2 expression were establised by using shRNA to MBD2 and scrambled control clones were established with scrambled control shRNA. To interrogate methylation changes induced by MBD2 knock-down we profiled three stably transfected scrambled control clones and three MBD2 knockdown clones on Illumina HumanMethylation450K arrays. Differential methylation analysis was carried out to identified CpG sites hypo-/hyper-methylated as a result of MBD2 knockdown.
2016-08-24 | E-GEOD-77201 | biostudies-arrayexpress
Project description:Cancer is characterised by DNA hypermethylation and gene silencing of CpG island-associated promoters, including tumour suppressor genes The methyl-CpG-binding domain (MBD) family of proteins bind to methylated DNA and can aid in the meditation of gene silencing by interaction with histone deacetylases and histone methyltransferases. However the mechanisms responsible for eliciting CpG island hypermethylation in cancer, and the potential role that MBD may proteins play in modulation of the methylome remain unclear. Our previous work demonstrated that MBD2 preferentially binds to the hypermethylated GSTP1 promoter CpG island in prostate cancer cells. Here, we use functional genetic approaches to investigate if MBD2 plays an active role in promoting DNA methylation. First, we show that loss of MBD2 results in inhibition of both maintenance and spread of de novo methylation of a transfected construct containing the GSTP1 promoter CpG island in prostate cancer cells and Mbd2-/- mouse fibroblasts. De novo methylation was rescued by transient expression of Mbd2 in Mbd2-/- cells. Second, we show that MBD2 depletion triggers significant hypomethylation genome-wide in prostate cancer cells with concomitant loss of MBD2 binding at promoter and enhancer regulatory regions. Finally, CpG islands and shores that become hypomethylated after MBD2 depletion in LNCaP cancer cells show significant hypermethylation in clinical prostate cancer, highlighting a potential active role of MBD2 in promoting cancer specific hypermethylation. Importantly, co-immunoprecipiation of MBD2 reveals that MBD2 associates with DNA methyltransferase (DNMT) enzymes 1 and 3A. Together our results demonstrate that MBD2 plays a critical role in ârewritingâ the cancer methylome at specific regulatory regions. LNCaP prostate cancer cell line clones with reduced MBD2 expression were establised by using shRNA to MBD2 and scrambled control clones were established with scrambled control shRNA. To interrogate expression changes induced by MBD2 knock-down we profiled three stably transfected scrambled control clones and three MBD2 knockdown clones on Affymetrix HuGene 1.0ST expression arrays. Differential expression analysis was carried out to identified genes up-/down-regulated by MBD2 knockdown.
2016-08-24 | E-GEOD-77187 | biostudies-arrayexpress
Project description:Cancer is characterised by DNA hypermethylation and gene silencing of CpG island-associated promoters, including tumour suppressor genes The methyl-CpG-binding domain (MBD) family of proteins bind to methylated DNA and can aid in the meditation of gene silencing by interaction with histone deacetylases and histone methyltransferases. However the mechanisms responsible for eliciting CpG island hypermethylation in cancer, and the potential role that MBD may proteins play in modulation of the methylome remain unclear. Our previous work demonstrated that MBD2 preferentially binds to the hypermethylated GSTP1 promoter CpG island in prostate cancer cells. Here, we use functional genetic approaches to investigate if MBD2 plays an active role in promoting DNA methylation. First, we show that loss of MBD2 results in inhibition of both maintenance and spread of de novo methylation of a transfected construct containing the GSTP1 promoter CpG island in prostate cancer cells and Mbd2-/- mouse fibroblasts. De novo methylation was rescued by transient expression of Mbd2 in Mbd2-/- cells. Second, we show that MBD2 depletion triggers significant hypomethylation genome-wide in prostate cancer cells with concomitant loss of MBD2 binding at promoter and enhancer regulatory regions. Finally, CpG islands and shores that become hypomethylated after MBD2 depletion in LNCaP cancer cells show significant hypermethylation in clinical prostate cancer, highlighting a potential active role of MBD2 in promoting cancer specific hypermethylation. Importantly, co-immunoprecipiation of MBD2 reveals that MBD2 associates with DNA methyltransferase (DNMT) enzymes 1 and 3A. Together our results demonstrate that MBD2 plays a critical role in “rewriting” the cancer methylome at specific regulatory regions.
2016-08-24 | GSE77187 | GEO
Project description:Cancer is characterised by DNA hypermethylation and gene silencing of CpG island-associated promoters, including tumour suppressor genes The methyl-CpG-binding domain (MBD) family of proteins bind to methylated DNA and can aid in the meditation of gene silencing by interaction with histone deacetylases and histone methyltransferases. However the mechanisms responsible for eliciting CpG island hypermethylation in cancer, and the potential role that MBD may proteins play in modulation of the methylome remain unclear. Our previous work demonstrated that MBD2 preferentially binds to the hypermethylated GSTP1 promoter CpG island in prostate cancer cells. Here, we use functional genetic approaches to investigate if MBD2 plays an active role in promoting DNA methylation. First, we show that loss of MBD2 results in inhibition of both maintenance and spread of de novo methylation of a transfected construct containing the GSTP1 promoter CpG island in prostate cancer cells and Mbd2-/- mouse fibroblasts. De novo methylation was rescued by transient expression of Mbd2 in Mbd2-/- cells. Second, we show that MBD2 depletion triggers significant hypomethylation genome-wide in prostate cancer cells with concomitant loss of MBD2 binding at promoter and enhancer regulatory regions. Finally, CpG islands and shores that become hypomethylated after MBD2 depletion in LNCaP cancer cells show significant hypermethylation in clinical prostate cancer, highlighting a potential active role of MBD2 in promoting cancer specific hypermethylation. Importantly, co-immunoprecipiation of MBD2 reveals that MBD2 associates with DNA methyltransferase (DNMT) enzymes 1 and 3A. Together our results demonstrate that MBD2 plays a critical role in “rewriting” the cancer methylome at specific regulatory regions.
2016-08-24 | GSE77201 | GEO
Project description:In our study we applied a genome-wide DNA methylation analysis approach, MethylCap-seq, to map the differentially methylated regions in 24 tumor and matched normal colon samples. In total, 2687 frequently hypermethylated and 468 frequently hypomethylated regions were identified, which include potential biomarkers for CRC diagnosis. Hypermethylation in the tumor samples was enriched at CpG islands and gene promoters, while hypomethylation was distributed throughout the genome. Using epigenetic data from human embryonic stem cells, we show that frequent differentially methylated regions (DMRs) coincide with bivalent loci in human embryonic stem cells. DNA methylation is commonly thought to lead to cancer gene related silencing, however integration of publically available expression analysis shows that 75% of the frequently hypermethylation genes were most likely already lowly or not expressed in normal tissue. Collectively, our study provides genome-wide DNA methylation maps of colon cancer, comprehensive lists of DMRs, and gives further clues on the role of aberrant DNA methylation in CRC formation. To investigate DNA methylation in CRC in a genome-wide unbiased fashion, we applied MethylCap-seq. This method involves capture of methylated DNA using the MBD domain of MeCP2, and subsequent next-generation Illumina sequencing of eluted DNA. In addition, we compared MethylCap with RNA-seq and ChIP-seq profiles of H3K4me3 and H3K27me3 for the colon cancer tumor cell line HCT116 (HCT116 WT) and the cell line of HCT116 with DNMT1 and DNMT3b knockout (HCT116 DKO).
2012-10-26 | E-GEOD-39068 | biostudies-arrayexpress
Project description:A large-scale characterization of the methylation states of candidate CpG islands (CGIs) throughout the gastric cancer methylome has not previously been conducted. Genome-wide DNA methylation profiles were compared between 4 metastatic and 4 non-metastatic gastric carcinomas (GCs) and their surgical margins (SMs). The GC genome showed significantly higher proportions of hypomethylation in the promoter and exon-1 regions, as well as increased hypermethylation of intragenic fragments when compared to SMs. Differential methylation was observed in CGIs near transcription start sites of 546 genes between GCs and SMs, and 601 genes between metastatic and non-metastatic GCs. From the list of differentially methylated CGIs, 68 candidate genes and 10 known tumor-related genes were selected for further characterization based on their known molecular function using DHPLC. Significant differential methylation was validated in the CGIs of 15 genes between GCs and SMs (Ps<0.05) and confirmed using bisulfite-sequencing. These genes include BMP3, BNIP3, CDKN2A, ECEL1, ELK1, GFRA1, HOXD10, KCNH1, PSMD10, PTPRT, SIGIRR, SRF, TBX5, TFPI2, and ZNF382. Hypomethylation of CGIs correlated with up-regulation of GFRA1 expression in GCs, while hypermethylation of other genes inactivated their transcription. Most importantly, prevalence of GFRA1, SRF, and ZNF382 methylation alterations were inversely and coordinately associated with GC metastasis and the patients’ overall survival throughout discovery and testing cohorts in China as well as independent validation cohorts in Japan and Korea. In conclusion, methylation changes in the CGIs of 15 genes correlated strongly with GC development. GFRA1 hypomethylation and SRF and ZNF382 hypermethylation are potential synergistic biomarkers for the prediction of GC metastasis. To identify differential methylation of CGIs related to GC development and metastasis, genome-wide DNA methylation changes in 8 pairs of GC and SM samples were analysed using the MCAM assay with a 99K custom-designed Agilent oligonucleotide microarray composed of 99,027 probes targeting 6,177 unique protein-coding genes containing at least two methylation-sensitive/insensitive SmaI/ XmaI restriction sites (CCC|GGG/ C|CmCGGG) as described in Shen et al, PLoS Genet 3, 2023-2036 (2007).
2014-06-02 | E-GEOD-47724 | biostudies-arrayexpress
Project description:Purpose: To establish pancreatic cancer-related aberrnat DNA methylation patterns, especially in CGI, CGI shore, orphan CGI and non-CGI promoter region and provide diagnosis or prognosis biomarker for pancreatic cancer dignosis or prognosis prediction Methods:MBD methylCap/seq was carried out to screen differentially methylated CpG islands in 3 libraries which includes 1 pancreatic cancer mix library, 1 adjacent normal tissue mix library and 1 normal pancreas tissue. MSP and multiplex-BSP validation was performed in independent tumor and adjacent tissues. Results: 66807 Hypermethylation DMR and 46815 Hypomethylation DMR were discovered in whole pancreatic cancer genome. 5280 Hypermethylation and 3488 Hypomethylation CpGI region were related gene promoter or gene body. Gene expression of 10 aberrant DMR were related with their methylation status validated by MSRE-qPCR and RT-PCR in 5-aza’ treated pancreatic cancer cell line. 40 DMR were validated in pancreatic cancer and adjacent tissues with MSP and gene ontology analysis showed seven of them were related with regulation of transcription(GO:0006355) which included DLX4,ELAVL2,IRX1,PITX2,SIM2,TBX5,TFAP2C. Conclusions: Methylcap-seq identified hundreds of DMR genes and regions which might involve with gene expression regulation and could be used as biological markers of pancreatic cancer therapy target or diagnosis.
2014-07-08 | GSE54854 | GEO