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KDM2B binds CpG islands and modulates recruitment of Ring1b

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE40860 | GEO | 2012/12/26

SECONDARY ACCESSION(S): PRJNA175125

REPOSITORIES: GEO

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KDM2B binds CpG islands and modulates recruitment of Ring1b

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

An epigenetic mark of polycomb response elements implemented by Trx/MLL/COMPASS

Project description:In Drosophila, Polycomb Response Elements (PREs) are identified as genomic sequences allowing the maintenance of transcriptional repression in the absence of the initiating signal. Although PREs in Drosophila are well characterized, the existence of mammalian PRE-like elements remains debated. Accumulating evidence supports a model in which CpG islands function to recruit Polycomb-Group complexes (PcG), however, it is not evident which subclasses of CpG islands serve as PREs. Trithorax (Trx), which is required for positive regulation of gene expression in Drosophila, is known to co-bind Drosophila PREs where it is thought to antagonize polycomb-dependent silencing of nearby genes. Here, we demonstrate the existence of Trx-dependent H3K4 dimethylation loci that specifically mark Drosophila PREs and are required for the maintenance of expression of the nearby genes. Similarly, in human cells, we find ~ 3000 MLL1 (human Trx homologue)-dependent H3K4 dimethylation loci, which correlate strongly with CpG island density. In the absence of MLL1 and H3K4 dimethylation at these loci, there is an increase in H3K27 trimethylation levels, suggesting these sites can recruit Polycomb Repressive Complex 2 (PRC2). By inhibiting PRC2-dependent silencing in the absence of MLL1, we establish that a balance exists between MLL1 and PRC2, and their respective capacity to maintain or repress transcription. Thus, by investigating a conserved function between Trx and MLL1, we provide rules for the identification of CpG island subclasses serving as PRE-like sequences within the human genome. To examine changes in histone-modification profiles and gene expression after depletion of Trx in Drosophila S2 cells, and MLL1 in human HCT116 cells. We also treated MLL1-NULL HCT116 cells with GSK126 (5uM) for 4 days and measured changes in gene expression.

2016-07-26 | E-GEOD-81795 | biostudies-arrayexpress

An epigenetic mark of polycomb response elements implemented by Trx/MLL/COMPASS

2016-07-26 | GSE81795 | GEO

Deletion of KDM2B DNA-binding domain affects RING1B and SUZ12 occupancy

Project description:The histone lysine demethylase protein, KDM2B, associates with the PCGF1/PRC1 complex and binds to non-methylated DNA through its ZF-CxxC domain, providing a possible molecular link between CpG island elements and polycomb nucleation (Farcas et al., 2012, Wu et al., 2013). Here, a novel genetic system was designed in which PCGF1/PRC1 targeting could be disrupted in vivo through the ablation of KDM2B-mediated DNA binding. To ablate PCGF1/PRC1 targeting, an exon that encodes most of the KDM2B ZF-CxxC domain and is shared by both the long and short form of the protein was flanked by loxP sites (Kdm2bfl/fl). Homozygous mouse ES cell lines were derived that also stably express a tamoxifen inducible form of CRE-recombinase. CRE induced deletion of the ZF-CxxC domain by the addition of tamoxifen yields KDM2B long and short form proteins that are incapable of binding to CpG island DNA but still remain associated with the PCGF1/PRC1 variant complex. We then assessed genome-wide occupancy of the PRC1 component RING1B and the PRC2 component SUZ12 to examine the impact of losing KDM2B-dependent targeting of polycomb. KDM2Bfl/fl ES cells were treated with 800M-BM-5M tamoxifen for 72hours and compared to untreated control cells by ChIP-seq for KDM2B, RING1B and SUZ12, and RNA-seq.

2014-05-27 | E-GEOD-52619 | biostudies-arrayexpress

Kdm2b maintains murine embryonic stem cell status by recruiting PRC1 complex to CpG islands of lineage genes [ChIP-Seq]

Project description:Polycomb group (PcG) proteins play important roles in repressing lineage-specific genes and maintaining the undifferentiated state of mouse embryonic stem cells (mESCs). However, the mechanisms by which PcG proteins are recruited to their targets are largely unknown. Here, we show that the histone demethylase Kdm2b is highly expressed in mESCs and regulated by the pluripotent factors Oct4/Sox2 directly. Depletion of Kdm2b in mESCs causes de-repression of lineage-specific genes and induces early differentiation. The function of Kdm2b depends on its CXXC-ZF domain, which mediates Kdm2b’s genome-wide binding to CpG islands (CGIs). Kdm2b interacts with the core components of the Polycomb repressive complex 1 (PRC1) and recruits the complex to the CGIs of early lineage-specific genes. Thus, our study not only reveals a novel Oct4/Sox2-Kdm2b-PRC1-CGI regulatory axis and its function in maintaining undifferentiated state of mESCs, but also demonstrates a critical function of Kdm2b in recruiting PRC1 to the CGIs of lineage-specific genes to repress their expression. In this dataset, we include the ChIP-seq data of Kdm2b, Ezh2 and Ring1b in both control and Kdm2b knock down mouse embryonbic stem cells.

2013-02-20 | E-GEOD-41314 | biostudies-arrayexpress

Deletion of KDM2B DNA-binding domain affects RING1B and SUZ12 occupancy

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Kdm2b maintains murine embryonic stem cell status by recruiting PRC1 complex to CpG islands of lineage genes [Expression profiling]

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2013-02-20 | E-GEOD-41298 | biostudies-arrayexpress

E2F6 initiates stable epigenetic silencing of germline genes during embryonic development

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.

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