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KDM2A and KDM2B cooperatively protect a subset of CpG Islands from DNA methylation [RRBS]

ABSTRACT: In the mammalian genome, most CpGs are methylated, however, regions of the genome known as CpG islands (CGIs) are largely unmethylated, which are closely associated with modulating gene expression. The KDM2 proteins (KDM2A and KDM2B) are recruited via their ZF-CxxC domains to CGIs and mediate demethylation of H3K36me2 at these regions. However, the mechanism whether and how KDM2 proteins protect CGIs from DNA methylation remains unknown. Here, we report that depletion of each or both KDM2 proteins, or mutation JmjC domains of KDM2 proteins, leads to a modest increase of DNA methylation at CGIs, but a significant increase at CGI shores. Depletion of both KDM2 proteins shows most obvious increase of DNA methylation, indicating that KDM2A and KDM2B cooperatively regulate DNA methylation at CGIs. We further show that DNA methylation in the absence of KDM2 proteins show more obvious increase at a subset of CpG Islands such as non-marked and H3K27me3-only CGIs than other CpG Islands like bivalent and H3K4me3-only CGIs. Taken together, our finding reveals the role for KDM2 proteins in regulating DNA methylation at CGIs, and uncovers the mechanism by which complex chromatin state including histone modifications and CGI binding proteins synergistically protect CGIs from DNA methylation.

ORGANISM(S): Mus musculus

PROVIDER: GSE180558 | GEO | 2025/12/22

REPOSITORIES: GEO

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KDM2A and KDM2B cooperatively protect a subset of CpG Islands from DNA methylation [ChIP-seq]

Project description:In the mammalian genome, most CpGs are methylated, however, regions of the genome known as CpG islands (CGIs) are largely unmethylated, which are closely associated with modulating gene expression. The KDM2 proteins (KDM2A and KDM2B) are recruited via their ZF-CxxC domains to CGIs and mediate demethylation of H3K36me2 at these regions. However, the mechanism whether and how KDM2 proteins protect CGIs from DNA methylation remains unknown. Here, we report that depletion of each or both KDM2 proteins, or mutation JmjC domains of KDM2 proteins, leads to a modest increase of DNA methylation at CGIs, but a significant increase at CGI shores. Depletion of both KDM2 proteins shows most obvious increase of DNA methylation, indicating that KDM2A and KDM2B cooperatively regulate DNA methylation at CGIs. We further show that DNA methylation in the absence of KDM2 proteins show more obvious increase at a subset of CpG Islands such as non-marked and H3K27me3-only CGIs than other CpG Islands like bivalent and H3K4me3-only CGIs. Taken together, our finding reveals the role for KDM2 proteins in regulating DNA methylation at CGIs, and uncovers the mechanism by which complex chromatin state including histone modifications and CGI binding proteins synergistically protect CGIs from DNA methylation.

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KDM2 proteins constrain transcription from CpG island gene promoters independently of their histone demethylase activity [ChIP-seq]

Project description:CpG islands (CGI) are associated with the majority of mammalian gene promoters and function to recruit chromatin modifying enzymes. It has therefore been proposed that CGIs regulate gene expression through chromatin-based mechanisms, however in most cases this has not been directly tested. Here, we reveal that the histone H3 lysine 36 (H3K36) demethylase activity of the CGI-binding KDM2 proteins contributes only modestly to the H3K36me2-depleted state at CGI-associated gene promoters and is dispensable for normal gene expression. Instead, we discover that KDM2 proteins play a widespread and demethylase-independent role in constraining gene expression from CGI-associated gene promoters. We further show that KDM2 proteins shape RNA Polymerase II occupancy but not chromatin accessibility at CGI-associated promoters. Together this reveals a demethylase-independent role for KDM2 proteins in transcriptional repression and uncovers a new function for CGIs in constraining gene expression.

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KDM2 proteins constrain transcription from CpG island gene promoters independently of their histone demethylase activity [RNA-seq]

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CpG islands recruit a histone H3 lysine 36 demethylase [Illumina sequencing data]

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

CpG islands recruit a histone H3 lysine 36 demethylase [Agilent data]

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).

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