An Essential Switch in Subunit Composition of a Chromatin Remodeling Complex during Neural Development

Howard Hughes Medical Institute and Department of Developmental Biology, Stanford University, Stanford, CA 94305, USA.
Neuron (Impact Factor: 15.05). 08/2007; 55(2):201-15. DOI: 10.1016/j.neuron.2007.06.019
Source: PubMed


Mammalian neural stem cells (NSCs) have the capacity to both self-renew and to generate all the neuronal and glial cell-types of the adult nervous system. Global chromatin changes accompany the transition from proliferating NSCs to committed neuronal lineages, but the mechanisms involved have been unclear. Using a proteomics approach, we show that a switch in subunit composition of neural, ATP-dependent SWI/SNF-like chromatin remodeling complexes accompanies this developmental transition. Proliferating neural stem and progenitor cells express complexes in which BAF45a, a Krüppel/PHD domain protein and the actin-related protein BAF53a are quantitatively associated with the SWI2/SNF2-like ATPases, Brg and Brm. As neural progenitors exit the cell cycle, these subunits are replaced by the homologous BAF45b, BAF45c, and BAF53b. BAF45a/53a subunits are necessary and sufficient for neural progenitor proliferation. Preventing the subunit switch impairs neuronal differentiation, indicating that this molecular event is essential for the transition from neural stem/progenitors to postmitotic neurons. More broadly, these studies suggest that SWI/SNF-like complexes in vertebrates achieve biological specificity by combinatorial assembly of their subunits.

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    • "transient amplifying progenitors (TAPs) and Doublecortin (DCX)+ neuroblasts (Figures S1D and S1E and data not shown). Importantly , we also observed the expression of BAF53a and BAF45a (Figures S1F and S1G; but not BAF45b and BAF53b, Figures S1H and S1I), subunits characterizing the neural-progenitor-specific BAF complexes (Lessard et al., 2007). Conversely, Pax6 immunoreactivity is largely restricted to neuroblasts in the SEZ and rostral migratory stream (RMS), where it colocalizes with Brg1 (Figures 1D and 1E). "

    Full-text · Dataset · Nov 2015
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    • "Understanding the roles of BAF complexes in murine neural development so far has been based on data from phenotypic analyses of neural cell-type-specific mouse mutants of genes encoding the ATPase subunit Brg1 and some other BAF subunits (Bischof et al., 2015; Lessard et al., 2007; Matsumoto et al., 2006; Ninkovic et al., 2013; Tuoc et al., 2013a; Vogel-Ciernia et al., 2013; Weider et al., 2012; Wu et al., 2007; Yu et al., 2013). In ATPase Brg1-deficient neural cells, other BAF subunits are expressed at normal levels and are incorporated into ATPase Brm-based complexes (Lessard et al., 2007). In addition, the loss of both Brg1 and Brm subunits does not affect the expression of other BAF subunits in cancer cell lines (Strobeck et al., 2002). "
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    ABSTRACT: BAF (Brg/Brm-associated factors) complexes play important roles in development and are linked to chromatin plasticity at selected genomic loci. Nevertheless, a full understanding of their role in development and chromatin remodeling has been hindered by the absence of mutants completely lacking BAF complexes. Here, we report that the loss of BAF155/BAF170 in double-conditional knockout (dcKO) mice eliminates all known BAF subunits, resulting in an overall reduction in active chromatin marks (H3K9Ac), a global increase in repressive marks (H3K27me2/3), and downregulation of gene expression. We demonstrate that BAF complexes interact with H3K27 demethylases (JMJD3 and UTX) and potentiate their activity. Importantly, BAF complexes are indispensable for forebrain development, including proliferation, differentiation, and cell survival of neural progenitor cells. Our findings reveal a molecular mechanism mediated by BAF complexes that controls the global transcriptional program and chromatin state in development.
    Full-text · Article · Nov 2015 · Cell Reports
    • "The CHD family of nucleosome remodelers is defined by ATPase proteins with chromodomains, which bind methylated lysine residues in histone tails (Lessard et al. 2007). CHD3/4 ATPases are essential for nucleosome remodeling activity in the Mi-2/NuRD complex. "
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    ABSTRACT: The intestinal epithelium is an ideal model system for the study of normal and pathological differentiation processes. The mammalian intestinal epithelium is a single cell layer comprising proliferative crypts and differentiated villi. The crypts contain both proliferating and quiescent stem cell populations that self-renew and produce all the differentiated cell types, which are replaced every 3-5 days. The genetics of intestinal development, homeostasis, and disease are well defined, but less is known about the contribution of epigenetics in modulating these processes. Epigenetics refers to heritable phenotypic traits, including gene expression, which are independent of mutations in the DNA sequence. We have known for several decades that human colorectal cancers contain hypomethylated DNA, but the causes and consequences of this phenomenon are not fully understood. In contrast, tumor suppressor gene promoters are often hypermethylated in colorectal cancer, resulting in decreased expression of the associated gene. In this review, we describe the role that epigenetics plays in intestinal homeostasis and disease, with an emphasis on results from mouse models. We highlight the importance of producing and analyzing next-generation sequencing data detailing the epigenome from intestinal stem cell to differentiated intestinal villus cell.
    No preview · Article · Jul 2015 · Cellular and Molecular Life Sciences CMLS
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