Article

Mbd3/NURD Complex Regulates Expression of 5-Hydroxymethylcytosine Marked Genes in Embryonic Stem Cells

Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
Cell (Impact Factor: 33.12). 12/2011; 147(7):1498-510. DOI: 10.1016/j.cell.2011.11.054
Source: PubMed

ABSTRACT Numerous chromatin regulators are required for embryonic stem (ES) cell self-renewal and pluripotency, but few have been studied in detail. Here, we examine the roles of several chromatin regulators whose loss affects the pluripotent state of ES cells. We find that Mbd3 and Brg1 antagonistically regulate a common set of genes by regulating promoter nucleosome occupancy. Furthermore, both Mbd3 and Brg1 play key roles in the biology of 5-hydroxymethylcytosine (5hmC): Mbd3 colocalizes with Tet1 and 5hmC in vivo, Mbd3 knockdown preferentially affects expression of 5hmC-marked genes, Mbd3 localization is Tet1-dependent, and Mbd3 preferentially binds to 5hmC relative to 5-methylcytosine in vitro. Finally, both Mbd3 and Brg1 are themselves required for normal levels of 5hmC in vivo. Together, our results identify an effector for 5hmC, and reveal that control of gene expression by antagonistic chromatin regulators is a surprisingly common regulatory strategy in ES cells.

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    • "It has recently been shown that 5hmC acts not only as an intermediate of DNA demethylation but also as an epigenetic mark that recruits DNA-binding proteins. For example, it has been shown that the Mbd3/NURD complex regulates expression of 5hmC-marked genes in embryonic stem cells (ESCs) (Yildirim et al., 2011). It has also been reported that MeCP2 binds to 5hmC that is enriched within active genes as well as accessible chromatin in the nervous system (Mellé n et al., 2012). "
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    • "Alternatively, BRG1 recruitment might be compromised by reduced NuRD recruitment to the b-globin locus in LDB1D4/5-expressing cells. Evidence has been presented for interaction between BRG1 and NuRD, and, furthermore, SWI/SNF and NuRD can each influence the occupancy of the other in different contexts (Datta et al. 2005; Ramirez-Carrozzi et al. 2006; Yildirim et al. 2011). "
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    • "It has been proposed that 5hmC serves as an intermediate in a biochemical pathway leading to demethylation, either passively or actively (Ito et al., 2010; He et al., 2011; Inoue and Zhang, 2011; Maiti and Drohat, 2011; Zhang et al., 2012). Alternatively, it could serve as a stable epigenetic mark (Valinluck et al., 2004; Frauer et al., 2011; Yildirim et al., 2011; Hashimoto et al., 2012) that diversifies the DNA methylation signal. It is almost certain that 5hmC participates in gene expression programing since it is particularly enriched in enhancers, transcription factor binding sites and at promoters or gene bodies of actively transcribed genes (Jin et al., 2011; Stroud et al., 2011; Wu et al., 2011; Szulwach et al., 2011a). "
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