Implications of CpG islands on chromosomal architectures and modes of global gene regulation
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PROVIDER: PRJNA319994 | ENA |
REPOSITORIES: ENA
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Project description:In this study, we present the critical implication of CpG islands (CGI) on the general rules for chromatin structural architectures and gene regulation mechanisms. Through integrative biological big data analyses, we found that the linear gene arrangements in chromosomes harbor the critical evidences for spatial gene segregation and different modes of gene localization between CGI-containing (CGI+) and CGI-less (CGI-) genes within the nucleus. CGI- genes, which are generally located within the nuclear periphery (chromosomal territories) as heterochromatin, are converted to euchromatin and internalized into the nuclear center only when activated. However, CGI-centered regulations keep CGI+ genes from heterochromatin formation and located within nuclear center regardless of their activities. We also show these different localization behaviors make CGI+ and CGI- genes to be regulated by distinct transcriptional regulation mechanisms: CGI- genes are regulated by local bindings of transcription factors, while CGI+ genes are strongly engaged in the 3-dimensional long-range chromosomal interactions. This SuperSeries is composed of the SubSeries listed below.
2018-02-15 | GSE80799 | GEO
Project description:CpG islands (CGIs) have long been implicated in the regulation of vertebrate gene expression. However, the involvement of CGIs in chromosomal architectures and associated gene expression regulations has not yet been thoroughly explored. By combining large-scale integrative data analyses and experimental validations, we show that CGIs clearly reconcile two competing models explaining nuclear gene localizations. We first identify CGI-containing (CGI+) and CGI-less (CGI-) genes are non-randomly clustered within the genome, which reflects CGI-dependent spatial gene segregation in the nucleus and corresponding gene regulatory modes. Regardless of their transcriptional activities, CGI+ genes are mainly located at the nuclear center and encounter frequent long-range chromosomal interactions. Meanwhile, nuclear peripheral CGI- genes forming heterochromatin are activated and internalized into the nuclear center by local enhancer-promoter interactions. Our findings demonstrate the crucial implications of CGIs on chromosomal architectures and gene positioning, linking the critical importance of CGIs in determining distinct mechanisms of global gene regulation in three-dimensional space in the nucleus.
| S-EPMC5961348 | biostudies-literature
Project description:CpG islands shape the epigenome landscape.
| PRJNA419733 | ENA
Project description:CpG island elements are associated with most mammalian gene promoters, yet how they contribute to gene regulation remains poorly understood. Recently it has become clear that a subset of CpG islands in embryonic stem cells can act as polycomb response elements and are recognized by the polycomb silencing systems to regulate the expression of genes involved in pluripotency and early developmental transcription programs. How CpG islands function mechanistically as nucleation sites for polycomb repressive complexes remains unknown. Here we discover that the KDM2B protein, by virtue of its ZF-CxxC DNA binding domain, specifically recognizes non-methylated DNA in CpG islands elements genome-wide. Through a physical interaction with the polycomb repressive complex 1 (PRC1), KDM2B targets PRC1 to CpG islands where it contributes to H2AK119ub1 and gene repression at a subset of polycomb targets. Unexpectedly, we also find that CpG islands are occupied by low levels of PRC1 throughout the genome, suggesting that the KDM2B-PRC1 complex may sample CpG island associated genes for susceptibility to polycomb mediated silencing. These observations demonstrate an unexpected and direct link between recognition of CpG islands by KDM2B and targeting of the polycomb repressive system. This provides the basis for a new model describing the functionality of CpG islands as mammalian PREs.
2012-12-26 | GSE40860 | GEO
Project description:CpG island elements are associated with most mammalian gene promoters, yet how they contribute to gene regulation remains poorly understood. Recently it has become clear that a subset of CpG islands in embryonic stem cells can act as polycomb response elements and are recognized by the polycomb silencing systems to regulate the expression of genes involved in pluripotency and early developmental transcription programs. How CpG islands function mechanistically as nucleation sites for polycomb repressive complexes remains unknown. Here we discover that the KDM2B protein, by virtue of its ZF-CxxC DNA binding domain, specifically recognizes non-methylated DNA in CpG islands elements genome-wide. Through a physical interaction with the polycomb repressive complex 1 (PRC1), KDM2B targets PRC1 to CpG islands where it contributes to H2AK119ub1 and gene repression at a subset of polycomb targets. Unexpectedly, we also find that CpG islands are occupied by low levels of PRC1 throughout the genome, suggesting that the KDM2B-PRC1 complex may sample CpG island associated genes for susceptibility to polycomb mediated silencing. These observations demonstrate an unexpected and direct link between recognition of CpG islands by KDM2B and targeting of the polycomb repressive system. This provides the basis for a new model describing the functionality of CpG islands as mammalian PREs. ChIP-Seq to compare KDM2A vs. KDM2B genome-wide binding profiles and to understand the contribution of KDM2B to RING1B nucleation. Binding of Kdm2a and Kdm2b to the genome was examined in wildtype mESC, and Kdm2b and Ring1b in mESC where Kdm2b has been stably knocked down by shRNA.
2012-12-26 | E-GEOD-40860 | biostudies-arrayexpress
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:This SuperSeries is composed of the following subset Series: GSE18588: CpG islands recruit a histone H3 lysine 36 demethylase [Illumina sequencing data] GSE21201: CpG islands recruit a histone H3 lysine 36 demethylase [Agilent data] Refer to individual Series
2010-04-26 | E-GEOD-21202 | 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:The lysine acetyltransferase KAT6A (MOZ, MYST3) belongs to the MYST family of chromatin regulators, facilitating histone acetylation. Dysregulation of KAT6A has been implicated in developmental syndromes and the onset of acute myeloid leukemia (AML). Previous work suggests that KAT6A is recruited to its genomic targets by a combinatorial function of histone binding PHD fingers, transcription factors and chromatin binding interaction partners. Here, we demonstrated that a winged helix domain at the N-terminus of KAT6A specifically interacts with unmethylated CpG motifs. This DNA binding function leads to the association of KAT6A to unmethylated CpG islands (CGIs) genome wide. Mutation of the essential amino acids completely abrogates the enrichment of KAT6A at CGIs. Overexpression of a KAT6A WH1 mutant has a dominant negative effect on H3K9 histone acetylation, which is comparable to the effects upon overexpression of a KAT6A HAT domain mutant. Taken together, our work revealed a previously unrecognized chromatin recruitment mechanism of KAT6A, offering a new perspective on the role of KAT6A in gene regulation and human diseases
2023-01-14 | PXD034833 | Pride
Project description:CpG-islands (CGIs) are key regulatory DNA elements at most promoters, but how they influence the chromatin status and transcription remains elusive. Here we identify and characterize SAMD1 (SAM domain-containing protein 1) as an unmethylated CGI-binding protein. SAMD1 possesses an atypical winged-helix domain that directly recognizes unmethylated CpG-containing DNA via simultaneous interactions with both the major and the minor groove. The SAM domain interacts with L3MBTL3, but it can also homopolymerize into a closed pentameric ring. At a genome-wide level, SAMD1 localizes to H3K4me3-decorated CGIs, where it acts as a repressor. SAMD1 tethers L3MBTL3 to chromatin and interacts with the KDM1A histone demethylase complex to modulate H3K4me2 and H3K4me3 levels at CGIs, thereby providing a mechanism for SAMD1-mediated transcriptional repression. Absence of SAMD1 impairs ES cell differentiation processes, leading to mis-regulation of key biological pathways. Together, our work establishes SAMD1 as a novel chromatin regulator acting at unmethylated CGIs.
2021-05-13 | PXD016781 | Pride