MBD2/NuRD and MBD3/NuRD, two distinct complexes with different biochemical and functional properties

Department of Molecular Biology, NCMLS M850/3.79, Radboud University, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands.
Molecular and Cellular Biology (Impact Factor: 4.78). 03/2006; 26(3):843-51. DOI: 10.1128/MCB.26.3.843-851.2006
Source: PubMed


The human genome contains a number of methyl CpG binding proteins that translate DNA methylation into a physiological response.
To gain insight into the function of MBD2 and MBD3, we first applied protein tagging and mass spectrometry. We show that MBD2
and MBD3 assemble into mutually exclusive distinct Mi-2/NuRD-like complexes, called MBD2/NuRD and MBD3/NuRD. We identified
DOC-1, a putative tumor suppressor, as a novel core subunit of MBD2/NuRD as well as MBD3/NuRD. PRMT5 and its cofactor MEP50
were identified as specific MBD2/NuRD interactors. PRMT5 stably and specifically associates with and methylates the RG-rich
N terminus of MBD2. Chromatin immunoprecipitation experiments revealed that PRMT5 and MBD2 are recruited to CpG islands in
a methylation-dependent manner in vivo and that H4R3, a substrate of PRMT, is methylated at these loci. Our data show that
MBD2/NuRD and MBD3/NuRD are distinct protein complexes with different biochemical and functional properties.

Download full-text


Available from: Michiel Vermeulen, Oct 03, 2015
34 Reads
  • Source
    • "Sin3, NuRD and CoREST (Brunmeir et al., 2009). Interestingly, it has been demonstrated that all of the above complexes have flexible composition, and may incorporate various histone methyltransferases such as Prmt5 (NuRD) (Le Guezennec et al., 2006), G9a (CoREST) (Lunyak et al., 2002; Roopra et al., 2004) or Lsd1 (CoREST, NODE) (Shi et al., 2004; Liang et al., 2008). Additionally, different subtypes of these complexes are targeted to specific DNA sequences via association with different transcription factors or DNA binding proteins; each complex is able to form associations with a number of different TFs (Brunmeir et al., 2009). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Prdm1 is a global repressor of transcription that plays multiple important roles during embryonic development, including neural crest specification. Prdm1 acts by repressing large sets of genes via sequence-specific recruitment of co-repressors, many of which are epigenetic modifiers. It is not known whether Prdm1 is expressed during neural crest development in chick embryo. Moreover, the mechanism of Prdm1 action or the nature of possible binding partners that mediate its effects in the neural crest had not yet been addressed. Prdm1 binding partners are known to play important roles during embryonic development, yet in many cases no spatiotemporal expression analysis during early vertebrate development has been performed. In this paper we report the expression patterns of Prdm1 and seven of its known or putative binding partners (Hdac1 and 2, Tle1 and 3, G9a, Prmt5, Lsd1) during early stages of chicken embryogenesis. Prdm1 is expressed in the neural plate border and premigratory neural crest during chick development. Six Prdm1 binding partners (except Tle1) are co-expressed with Prdm1 in the prospective neural plate border at HH4-HH6, and all seven show strong and specific expression in the neural plate border at HH7-HH8, suggesting all of them may cooperate with Prdm1 during neural crest development in chick embryos. Copyright © 2014. Published by Elsevier B.V.
    Gene Expression Patterns 02/2015; 17(1). DOI:10.1016/j.gep.2014.12.003 · 1.38 Impact Factor
  • Source
    • "While the precise distribution of subunits across NuRD complexes is not well understood, multiple complexes have been shown to exist that contain some combination of the core subunits. For example, NuRD complexes have been isolated that contain either MBD2 or MBD3 but not both [19]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Loss of the chromatin remodeling ATPase CHD5 has been linked to the progression of neuroblastoma tumors, yet the underlying mechanisms behind the tumor suppressor role of CHD5 are unknown. In this study, we purified the human CHD5 complex and found that CHD5 is a component of the full NuRD transcriptional repressor complex, which also contains methyl-CpG binding proteins and histone deacetylases. The CHD5/NuRD complex appears mutually exclusive with the related CHD4/NuRD complex as overexpression of CHD5 results in loss of the CHD4 protein in cells. Following a search for genes that are regulated by CHD5 in neuroblastoma cells, we found that CHD5 binds to and represses the G2/M checkpoint gene WEE1. Reintroduction of CHD5 into neuroblastoma cells represses WEE1 expression, demonstrating that CHD5 can function as a repressor in cells. A catalytically inactive mutant version of CHD5 is able to associate with a NuRD cofactor but fails to repress transcription. Our study shows that CHD5 is a NuRD-associated transcriptional repressor and identifies WEE1 as one of the CHD5-regulated genes that may link CHD5 to tumor suppression.
    PLoS ONE 09/2014; 9(9):e108066. DOI:10.1371/journal.pone.0108066 · 3.23 Impact Factor
  • Source
    • "Although it has been widely shown that MBD2 selectively binds methylated DNA in vitro [21], [22] the proof that this also occurs in vivo was only recently provided by genome wide binding of MBD2 and other family members by comprehensive chromatin immunoprecipitation (ChIP) sequencing [23], [24]. Genome wide mapping of MBD2 binding in mouse embryonic stem cells showed that in vivo binding predominantly occurs at highly methylated, CpG dense regions, although a subset of binding sites was detected at active unmethylated promoters. "
    [Show abstract] [Hide abstract]
    ABSTRACT: MBD2 is a subunit of the NuRD complex that is postulated to mediate gene repression via recruitment of the complex to methylated DNA. In this study we adopted an MBD2 tagging-approach to study its genome wide binding characteristics. We show that in vivo MBD2 is mainly recruited to CpG island promoters that are highly methylated. Interestingly, MBD2 binds around 1 kb downstream of the transcription start site of a subset of ∼400 CpG island promoters that are characterized by the presence of active histone marks, RNA polymerase II (Pol2) and low to medium gene expression levels and H3K36me3 deposition. These tagged-MBD2 binding sites in MCF-7 show increased methylation in a cohort of primary breast cancers but not in normal breast samples, suggesting a putative role for MBD2 in breast cancer.
    PLoS ONE 06/2014; 9(6):e99603. DOI:10.1371/journal.pone.0099603 · 3.23 Impact Factor
Show more