Homo sapiens
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ABSTRACT:
PROVIDER: PRJNA139361 | ENA |
REPOSITORIES: ENA
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Project description:Aberrant DNA methylation is induced at specific promoter CpG islands (CGIs) in contrast with mutations. The specificity is influenced by genome architecture and epigenetic factors, but their relationship is still unknown. In this study, we isolated promoter CGIs susceptible and resistant to aberrant methylation induction during prostate and breast carcinogenesis. The effect of genome architecture was more evident for promoter CGIs susceptible in both of the two tissues than for promoter CGIs susceptible only in one tissue. Multivariate analysis of promoter CGIs with tissue-nonspecific susceptibility showed that genome architecture, namely a remote location from SINE (OR=5.98; 95% CI=2.33-15.34) and from LINE (OR=2.08; 95% CI=1.03-4.21), was associated with increased susceptibility, independent of epigenetic factors such as the presence of RNA polymerase II (OR=0.09; 95% CI=0.02-0.48) and H3K27me3 (OR=3.28; 95% CI=1.17-9.21). These results showed that methylation susceptibility of promoter CGIs is determined both by genome architecture and epigenetic factors, independently.
2011-06-06 | GSE28284 | GEO
Project description:Eukaryotic gene expression profiles are largely defined by transcription factors that recognize specific DNA sequences in gene regulatory regions and impact RNA polymerase recruitment and transcription. In addition to specific core promoter regulatory elements, up to 70% of genes in higher eukaryotes are also characterized by an overrepresentation of cytosine/guanine base pairs (CpGs) surrounding promoters and gene regulatory units. These features, called CpG islands, were identified over twenty years ago but there remains little mechanistic evidence to suggest how these enigmatic elements contribute to promoter function, with the exception that they are refractory to epigenetic silencing by DNA methylation. Here we uncover a role for CpG islands in buffering gene regulatory elements from repressive histone H3 lysine 36 methylation by directly recruiting the H3K36 specific lysine demethylase enzyme KDM2A. KDM2A is recruited to CpG islands by a zinc finger CxxC (ZF-CxxC) domain that specifically recognizes CpG DNA and is blocked by DNA methylation. This capacity to sense the epigenetic methylation state of DNA constrains KDM2A to non-methylated CpG islands. Importantly, these observations suggest CpG islands may function to delineate gene regulatory elements from bulk chromatin by recruiting factors that create unique chromatin architecture. This study provides information about binding of lysine demethylase enzyme KDM2A in mouse embryonic stem cells.
2010-04-27 | E-GEOD-18588 | biostudies-arrayexpress
Project description:Eukaryotic gene expression profiles are largely defined by transcription factors that recognize specific DNA sequences in gene regulatory regions and impact RNA polymerase recruitment and transcription. In addition to specific core promoter regulatory elements, up to 70% of genes in higher eukaryotes are also characterized by an overrepresentation of cytosine/guanine base pairs (CpGs) surrounding promoters and gene regulatory units. These features, called CpG islands, were identified over twenty years ago but there remains little mechanistic evidence to suggest how these enigmatic elements contribute to promoter function, with the exception that they are refractory to epigenetic silencing by DNA methylation. Here we uncover a role for CpG islands in buffering gene regulatory elements from repressive histone H3 lysine 36 methylation by directly recruiting the H3K36 specific lysine demethylase enzyme KDM2A. KDM2A is recruited to CpG islands by a zinc finger CxxC (ZF-CxxC) domain that specifically recognizes CpG DNA and is blocked by DNA methylation. This capacity to sense the epigenetic methylation state of DNA constrains KDM2A to non-methylated CpG islands. Importantly, these observations suggest CpG islands may function to delineate gene regulatory elements from bulk chromatin by recruiting factors that create unique chromatin architecture.
2010-04-27 | GSE18588 | GEO
Project description:In mouse development, long-term silencing by CpG island DNA methylation is specifically targeted to germline genes, however the molecular mechanisms of this specificity remain unclear. Here we demonstrate that the transcription factor E2F6, a member of the polycomb repressive complex 1.6 (PRC1.6), is critical to target and initiate epigenetic silencing at germline genes in early embryogenesis. Genome-wide, E2F6 binds preferentially to CpG islands in embryonic cells. E2F6 cooperates with MGA to silence a subgroup of germline genes in mouse embryonic stem cells and in vivo, a function that critically depends on the E2F6 marked box domain. Inactivation of E2f6 leads to a failure to deposit CpG island DNA methylation at these genes during implantation. Furthermore, E2F6 is required to initiate epigenetic silencing in early embryonic cells but becomes dispensable for the maintenance in differentiated cells. Our findings elucidate the mechanisms of epigenetic targeting of germline genes and provide a paradigm for how transient repression signals by DNA-binding factors in early embryonic cells are translated into long term epigenetic silencing during mammalian development.
2021-04-22 | PXD023974 | Pride
Project description:Transcription factors that bind small DNA motifs embedded in promoters play a central role in controlling gene expression. However, in addition to these elements, up to 70% of genes in higher eukaryotes also have high levels of non-methylated cytosine/guanine base pairs (CpGs) surrounding promoters and gene regulatory units. These features, called CpG islands, were identified over twenty years ago but there remains little mechanistic evidence to suggest how these enigmatic elements contribute to promoter function, with the exception that they are refractory to epigenetic silencing by DNA methylation. Here we show that CpG islands directly recruit the H3K36 specific lysine demethylase enzyme KDM2A. Genome wide analyses by ChIP-seq demonstrated a striking global association of KDM2A with CpG islands. Nucleation of KDM2A at these elements resulted in removal of H3K36 methylation creating CpG island chromatin that is uniquely depleted of this modification. KDM2A utilizes a zinc finger CxxC (ZF-CxxC) domain that specifically recognizes non-methylated CpG DNA and binding is blocked when the CpG DNA is methylated, thus constraining KDM2A to nonmethylated CpG islands. These data expose a remarkably straightforward mechanism through which KDM2A delineates a unique architecture that differentiates CpG island chromatin from bulk chromatin.
2010-04-27 | GSE21201 | GEO
Project description:Transcription factors that bind small DNA motifs embedded in promoters play a central role in controlling gene expression. However, in addition to these elements, up to 70% of genes in higher eukaryotes also have high levels of non-methylated cytosine/guanine base pairs (CpGs) surrounding promoters and gene regulatory units. These features, called CpG islands, were identified over twenty years ago but there remains little mechanistic evidence to suggest how these enigmatic elements contribute to promoter function, with the exception that they are refractory to epigenetic silencing by DNA methylation. Here we show that CpG islands directly recruit the H3K36 specific lysine demethylase enzyme KDM2A. Genome wide analyses by ChIP-seq demonstrated a striking global association of KDM2A with CpG islands. Nucleation of KDM2A at these elements resulted in removal of H3K36 methylation creating CpG island chromatin that is uniquely depleted of this modification. KDM2A utilizes a zinc finger CxxC (ZF-CxxC) domain that specifically recognizes non-methylated CpG DNA and binding is blocked when the CpG DNA is methylated, thus constraining KDM2A to nonmethylated CpG islands. These data expose a remarkably straightforward mechanism through which KDM2A delineates a unique architecture that differentiates CpG island chromatin from bulk chromatin. Two cell lines were used in this study: a control line (LMP) with wildtype levels of KDM2A, and a KDM2A knockdown line (RNAi) in which KDM2A levels were depleted by approximately 60% using an shRNA-based approach. For each cell line, RNA was extracted from cells collected on two different dates (rep1 and rep2).
2010-05-27 | E-GEOD-21201 | biostudies-arrayexpress
Project description:X chromosome inactivation (XCI) is a dosage compensation mechanism that silences the majority of genes on one X chromosome in each female cell. In order to characterize epigenetic changes that accompany this process, we measured DNA methylation levels in both 45,X Turner syndrome patients, who carry a single active X chromosome (Xa) and normal 46,XX females, who carry one Xa and one inactive X (Xi). Methylated DNA was immunoprecipitated and hybridized to tiling oligonucleotide arrays, generating epigenetic profiles of active and inactive X chromosomes. We observed that XCI is accompanied by changes in DNA methylation specifically at CpG islands. While the majority of CpG islands show increased methylation levels on the Xi, XCI results in reduced methylation at ~20% of CpG islands. Both intra- and inter-genic CpG islands are epigenetically modified, with the biggest increase in methylation occuring at the promoters of genes silenced by XCI. In contrast, genes escaping XCI have low levels of promoter methylation, while genes that undergo polymorphic silencing show intermediate increases in methylation proportionate to their frequency of inactivation. Thus promoter methylation and susceptibility to XCI are correlated. We observed a global correlation between CpG island methylation and the evolutionary age of different X chromosome strata, and that genes escaping XCI show increased methylation within gene bodies. We utilized our epigenetic map to predict both novel genes escaping XCI, and to identify sequence features that may contribute to the XCI process. Finally, as our study included Turner syndrome patients with single X chromosomes of both maternal and paternal origin we searched for parent-of-origin specific methylation differences, but found no evidence to support imprinting on the human X chromosome. Our study provides the first epigenetic profile of active and inactive X chromosomes, giving novel insights into the phenomenon of dosage compensation.
2010-07-20 | GSE22551 | GEO
Project description:X chromosome inactivation (XCI) is a dosage compensation mechanism that silences the majority of genes on one X chromosome in each female cell. In order to characterize epigenetic changes that accompany this process, we measured DNA methylation levels in both 45,X Turner syndrome patients, who carry a single active X chromosome (Xa) and normal 46,XX females, who carry one Xa and one inactive X (Xi). Methylated DNA was immunoprecipitated and hybridized to tiling oligonucleotide arrays, generating epigenetic profiles of active and inactive X chromosomes. We observed that XCI is accompanied by changes in DNA methylation specifically at CpG islands. While the majority of CpG islands show increased methylation levels on the Xi, XCI results in reduced methylation at ~20% of CpG islands. Both intra- and inter-genic CpG islands are epigenetically modified, with the biggest increase in methylation occuring at the promoters of genes silenced by XCI. In contrast, genes escaping XCI have low levels of promoter methylation, while genes that undergo polymorphic silencing show intermediate increases in methylation proportionate to their frequency of inactivation. Thus promoter methylation and susceptibility to XCI are correlated. We observed a global correlation between CpG island methylation and the evolutionary age of different X chromosome strata, and that genes escaping XCI show increased methylation within gene bodies. We utilized our epigenetic map to predict both novel genes escaping XCI, and to identify sequence features that may contribute to the XCI process. Finally, as our study included Turner syndrome patients with single X chromosomes of both maternal and paternal origin we searched for parent-of-origin specific methylation differences, but found no evidence to support imprinting on the human X chromosome. Our study provides the first epigenetic profile of active and inactive X chromosomes, giving novel insights into the phenomenon of dosage compensation. Methylated DNA was enriched by immunoprecipitation using antibodies against 5-methylcytosine. meDIP and input DNA was labeled with cy5 and cy3 respectively and hybridized to Nimblegen arrays comprising 2.1 million 50-85mers covering human chromosomes 20, 21, 22, X and Y at a mean density of ~1 probe per 100bp. Resulting log2 fluorescence ratios correspond to methylation levels. Seven patients with Turner syndrome (45,X karyotype), and three normal females (46,XX karyotype) were analyzed. Of the Turner syndrome cases, four had a maternally-derived X, and three had a paternally-derived X chromosome.
2010-07-20 | E-GEOD-22551 | biostudies-arrayexpress
Project description:Histone H3 mono-ubiquitination, catalyzed by the RING E3 ubiquitin ligase UHRF1, is appreciated as a docking site for DNMT1 during DNA replication to facilitate DNA methylation maintenance. Its functions beyond this are unknown. Here, we identify simultaneous increases in UHRF1-dependent H3K18ub and SUV39H1/2-dependent H3K9me3 as prominent epigenetic alterations accompanying DNA hypomethylation induced by DNMT1 inhibition. Integrative epigenomics analyses reveal that transient accumulation of hemi-methylated DNA, resulting from incomplete DNA methylation maintenance, stimulates UHRF1-dependent H3K18ub at CpG islands that nucleates new domains of H3K9me3 and impedes PRC2 activity in these genomic regions. Notably, H3K18ub enhances the methyltransferase activity of SUV39H1/2, leading to increased H3K9me3 at these CpG island promoters. Blocking H3K18ub-dependent SUV39H1/2 activity enhances the efficacy of DNMT1 inhibitors. Collectively, these findings reveal a novel histone ubiquitination-methylation crosstalk mechanism that reinforces heterochromatin states in the absence of DNA methylation and proposes new strategies for improving cancer epigenetic therapy.
2024-12-02 | PXD049993 | Pride
Project description:Methylation of CpG islands associated with genes can affect the expression of the proximal gene, and methylation of non associated CpG islands correlates to genomic instability. This epigenetic modification has been shown to be important in many pathologies, from development and disease to cancer. We report the development of a novel high-resolution microarray that detects the methylation status of over 25,000 CpG islands in the human genome. Experiments were performed to demonstrate low system noise in the methodology and that the array probes have a high signal to noise ratio. Methylation measurements between different cell lines were validated demonstrating the accuracy of measurement. We then identified alterations in CpG islands, both those associated with gene promoters, as well as non-promoter associated islands in a set of breast and ovarian tumors. We demonstrate that this methodology accurately identifies methylation profiles in cancer and in principle it can differentiate any CpG methylation alterations and can be adapted to analyze other species.
2009-04-28 | GSE15747 | GEO