NuRD and Pluripotency: A Complex Balancing Act

Laboratory of Molecular Carcinogenesis, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA.
Cell stem cell (Impact Factor: 22.27). 05/2012; 10(5):497-503. DOI: 10.1016/j.stem.2012.04.011
Source: PubMed


Embryonic stem cells (ESCs) are defined by two essential features--pluripotency and self-renewal--whose balance requires the concerted action of signal transduction pathways, transcription factor networks, and epigenetic regulators. Recent findings have implicated the NuRD chromatin remodeling complex in the sophisticated choreography of ESC regulatory pathways.

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Available from: Paul A Wade, May 20, 2014
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    • "The authors found that rather than silencing pluripotency-associated genes, NuRD is required to restrict transcript levels below a threshold, thereby sensitizing cells to differentiation cues and facilitating lineage commitment in response to the relevant stimuli (Reynolds et al., 2012a). Thus, NuRD and other repressive complexes might not function as traditional silencers but rather by fine-tuning expression levels of their target genes (Hu and Wade, 2012; Reynolds et al., 2013). "
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    ABSTRACT: The chromatin environment is essential for the correct specification and preservation of cell identity through modulation and maintenance of transcription patterns. Many chromatin regulators are required for development, stem cell maintenance, and differentiation. Here, we review the roles of the polycomb repressive complexes, PRC1 and PRC2, and the HDAC1- and HDAC2-containing complexes, NuRD, Sin3, and CoREST, in stem cells, development, and cancer, as well as the ongoing efforts to develop therapies targeting these complexes in human cancer. Furthermore, we discuss the role of repressive complexes in modulating thresholds for gene activation and their importance for specification and maintenance of cell fate.
    Cell Stem Cell 06/2014; 14(6):735-751. DOI:10.1016/j.stem.2014.05.006 · 22.27 Impact Factor
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    • "The network is centred by the pluripotent transcription factors OCT4, NANOG and SOX2, which act in a coordinated manner with chromatin modifying complexes (1,3). These complexes include Polycomb repressor complexes (PRC) 1 and 2, BRG1 associated factors (esBAF) complex and the nucleosomal remodelling and deacetylase (NuRD) complex (1,4). "
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    ABSTRACT: Pluripotency of embryonic stem cells (ESCs) is maintained by transcriptional activities and chromatin modifying complexes highly organized within the chromatin. Although much effort has been focused on identifying genome-binding sites, little is known on their dynamic association with chromatin across cell divisions. Here, we used a modified version of the iPOND (isolation of proteins at nascent DNA) technology to identify a large protein network enriched at nascent DNA in ESCs. This comprehensive and unbiased proteomic characterization in ESCs reveals that, in addition to the core replication machinery, proteins relevant for pluripotency of ESCs are present at DNA replication sites. In particular, we show that the chromatin remodeller HDAC1–NuRD complex is enriched at nascent DNA. Interestingly, an acute block of HDAC1 in ESCs leads to increased acetylation of histone H3 lysine 9 at nascent DNA together with a concomitant loss of methylation. Consistently, in contrast to what has been described in tumour cell lines, these chromatin marks were found to be stable during cell cycle progression of ESCs. Our results are therefore compatible with a rapid deacetylation-coupled methylation mechanism during the replication of DNA in ESCs that may participate in the preservation of pluripotency of ESCs during replication.
    Nucleic Acids Research 05/2014; 42(11). DOI:10.1093/nar/gku374 · 9.11 Impact Factor
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    • "This uncovered a convergence of SMAD2/3 signaling with the Hippo pathway and the pluripotency factor OCT4 to form the TSO complex. In hESCs, TSO occupies pluripotency-associated genes such as NANOG and OCT4, as well as ME genes, and represses gene expression via interaction with the NuRD corepressor complex, in agreement with recent reports showing a balancing function of NuRD in pluripotent cells (Hu and Wade, 2012; Reynolds et al., 2012). Thus, in pluripotency conditions the TSO provides a buffering capacity on pluripotency genes, while keeping the ME program silent. "
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    ABSTRACT: A small toolkit of morphogens is used repeatedly to direct development, raising the question of how context dictates interpretation of the same cue. One example is the transforming growth factor β (TGF-β) pathway that in human embryonic stem cells fulfills two opposite functions: pluripotency maintenance and mesendoderm (ME) specification. Using proteomics coupled to analysis of genome occupancy, we uncover a regulatory complex composed of transcriptional effectors of the Hippo pathway (TAZ/YAP/TEAD), the TGF-β pathway (SMAD2/3), and the pluripotency regulator OCT4 (TSO). TSO collaborates with NuRD repressor complexes to buffer pluripotency gene expression while suppressing ME genes. Importantly, the SMAD DNA binding partner FOXH1, a major specifier of ME, is found near TSO elements, and upon fate specification we show that TSO is disrupted with subsequent SMAD-FOXH1 induction of ME. These studies define switch-enhancer elements and provide a framework to understand how cellular context dictates interpretation of the same morphogen signal in development.
    Cell Reports 12/2013; 5(6). DOI:10.1016/j.celrep.2013.11.021 · 8.36 Impact Factor
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