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Methylation-dependent and -independent genomic targeting principles of the MBD protein family

ABSTRACT: In order to gain insight into DNA methylation readout, we have established a controlled strategy for profiling genomic targeting of chromatin-interacting factors in vivo. With this approach we determined binding preferences for the methyl-CpG binding domain (MBD) family of proteins, including disease relevant mutants, deletions and isoforms. In vivo binding of MBD proteins occurs as a linear function of local methylation density, and is dependent on functional MBD domain M-bM-^@M-^S methyl-CpG interactions. This directs specificity of MBD proteins to methylated, CpG dense and inactive regulatory regions. In contrast, binding to unmethylated sites is MBD protein specific and mediated via alternative domains or protein-protein interactions. The latter is observed for NuRD complex-mediated MBD2 tethering to a subset of unmethylated, tissue-specific regulatory regions, similar to MBD3. These functional binding maps reveal methylation-dependent and -independent binding modes determined by distinct protein domains and revise current models of DNA methylation readout through MBD proteins. Comparative binding analysis for the MBD family of proteins utilizing recombinase-assisted mapping of biotin-tagged proteins (RAMBiO). This set contains maps for 29 samples including wild type MBD proteins, mutants and domain variants in mouse ES cells, derived neurons (NP and TN) and Dnmt1/3a/3b triple-KO ES cells (TKO).

ORGANISM(S): Mus musculus

SUBMITTER: Dirk Schuebeler

PROVIDER: E-GEOD-39610 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Methylation-dependent and -independent genomic targeting principles of the MBD protein family

Project description:In order to gain insight into DNA methylation readout, we have established a controlled strategy for profiling genomic targeting of chromatin-interacting factors in vivo. With this approach we determined binding preferences for the methyl-CpG binding domain (MBD) family of proteins, including disease relevant mutants, deletions and isoforms. In vivo binding of MBD proteins occurs as a linear function of local methylation density, and is dependent on functional MBD domain – methyl-CpG interactions. This directs specificity of MBD proteins to methylated, CpG dense and inactive regulatory regions. In contrast, binding to unmethylated sites is MBD protein specific and mediated via alternative domains or protein-protein interactions. The latter is observed for NuRD complex-mediated MBD2 tethering to a subset of unmethylated, tissue-specific regulatory regions, similar to MBD3. These functional binding maps reveal methylation-dependent and -independent binding modes determined by distinct protein domains and revise current models of DNA methylation readout through MBD proteins.

2013-04-01 | GSE39610 | GEO

The SAM domain-containing protein 1 (SAMD1) acts as a repressive chromatin regulator at unmethylated CpG islands

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

Evidence that direct inhibition of transcription factor binding is the prevailing mode of gene and repeat repression by DNA methylation [RNA-Seq]

Project description:Cytosine methylation efficiently silences CpG-rich regulatory regions of genes and repeats in mammalian genomes. To what extent this entails direct inhibition of transcription factor (TF) binding versus indirect inhibition via recruitment of Methyl-CpG Binding Domain (MBD) proteins is unclear. Here we show that combinatorial genetic deletions of all four proteins with functional MBDs in mouse stem cells, derived neurons or a human cell line does not reactivate genes or repeats with methylated promoters. These do however become activated by methylation-restricted TFs if DNA methylation is removed. We identify several causal TFs in neurons, including ONECUT1, which is methylation-sensitive only at a motif variant. Rampantly upregulated retrotransposons in methylation-free neurons feature a CRE motif, which activates them in absence of DNA methylation via methylation-sensitive binding of CREB1. Our study reveals methylation-sensitive TFs in vivo and argues that direct inhibition, rather than indirect repression by the tested MBD proteins, is the prevailing mechanism of methylation-mediated repression at regulatory regions and repeats.

2022-09-29 | GSE184469 | GEO

Evidence that direct inhibition of transcription factor binding is the prevailing mode of gene and repeat repression by DNA methylation [ChIP-Seq]

2022-09-29 | GSE184468 | GEO

Evidence that direct inhibition of transcription factor binding is the prevailing mode of gene and repeat repression by DNA methylation [ATAC-Seq]

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Evidence that direct inhibition of transcription factor binding is the prevailing mode of gene and repeat repression by DNA methylation [WGBS-Seq]

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DNA methylation in aging BXD mouse strains

Project description:We performed affinity-based enrichment with methyl-CpG binding domain protein followed by high-throughput sequencing (MBD-seq) to assay DNA methylation in mouse liver tissue.

2020-07-06 | GSE137277 | GEO

DNA methylation in mouse liver tissue

Project description:We performed affinity-based enrichment with methyl-CpG binding domain protein followed by high-throughput sequencing (MBD-seq) to assay DNA methylation in mouse liver tissue.

2017-02-27 | GSE95361 | GEO

DNA methylation variability in a pilot study group with ischemic stroke

Project description:Elevated plasma homocysteine is an independent risk factor for cardiovascular disease and stroke, however the etiology remains poorly understood. Elevated homocysteine is known to inhibit methyltransferases including DNA methyltransferases, but no methylome-wide analysis of elevated homocysteine has been reported. Peripheral blood genomic DNA methylation in 8 Singaporean-Chinese ischemic stroke patients (4 male, 4 female) with varying homocysteine titer and hypertensive status were profiled using methyl-CpG binding domain (MBD) protein-enriched genome sequencing (MBD-seq) on Illumina Genome Analyzer IIx. A methylome wide screen was undertaken for gender, total plasma homocysteine, hypertension and age. The data show considerable variability within the small cohort, including at genes which are related to one carbon metabolism and cardiovascular disease. Peripheral blood genomic DNA methylation in 8 Singaporean-Chinese ischemic stroke patients (4 male, 4 female) was profiled using methyl-CpG binding domain (MBD) protein-enriched genome sequencing (MBD-seq) on Illumina Genome Analyzer IIx. Methylation parrterns were correlated with homocysteine levels, lypertensive status, gender and age.

2014-05-27 | E-GEOD-57962 | biostudies-arrayexpress

DNA methylation is required for chromatin binding by Mbd2 and Mbd3 in ES cells (ChIP-Seq, meDIP-seq and hmDIP-seq)

Project description:Cytosine methylation on DNA is an important epigenetic and regulatory mark. Chromatin remodeling complexes containing methyl-CpG binding domain (MBD) proteins modulate chromatin structure and transcription at methylated loci. Two MBD proteins, Mbd2 and Mbd3, are mutually exclusive members of the NuRD chromatin remodeling complex, and have been shown to bind methylated or hydroxymethylated DNA, respectively. However, a recent study called both results into question, showing that chromatin binding by these proteins is partially (Mbd2) or completely (Mbd3) independent of DNA methylation/hydroxymethylation. Here we re-analyze these data and observe discrepancies with both conclusions. Furthermore, we describe multiple new datasets that demonstrate the dependence of endogenous Mbd2 and Mbd3 on DNA methylation. Interestingly, we find that Mbd2 and Mbd3 are also dependent on one another for binding, likely due to the fact that both are required for normal levels of DNA methylation/hydroxymethylation. These findings describe a regulatory loop controlling the DNA methylation machinery and its readers.

2016-11-15 | GSE79770 | GEO

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