Corepressor for element-1–silencing transcription factor preferentially mediates gene networks underlying neural stem cell fate decisions

Institute for Brain Disorders and Neural Regeneration, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 09/2010; 107(38):16685-90. DOI: 10.1073/pnas.0906917107
Source: PubMed


The repressor element-1 (RE1) silencing transcription factor/neuron-restrictive silencer factor (REST/NRSF) silences neuronal genes in neural stem cells (NSCs) and nonneuronal cells through its role as a dynamic modular platform for recruitment of transcriptional and epigenetic regulatory cofactors to RE1-containing promoters. In embryonic stem cells, the REST regulatory network is highly integrated with the transcriptional circuitry governing self-renewal and pluripotency, although its exact functional role is unclear. The C-terminal cofactor for REST, CoREST, also acts as a modular scaffold, but its cell type-specific roles have not been elucidated. We used chromatin immunoprecipitation-on-chip to examine CoREST and REST binding sites in NSCs and their proximate progenitor species. In NSCs, we identified a larger number of CoREST (1,820) compared with REST (322) target genes. The majority of these CoREST targets do not contain known RE1 motifs. Notably, these CoREST target genes do play important roles in pluripotency networks, in modulating NSC identity and fate decisions and in epigenetic processes previously associated with both REST and CoREST. Moreover, we found that NSC-mediated developmental transitions were associated primarily with liberation of CoREST from promoters with transcriptional repression favored in less lineage-restricted radial glia and transcriptional activation favored in more lineage-restricted neuronal-oligodendrocyte precursors. Clonal NSC REST and CoREST gene manipulation paradigms further revealed that CoREST has largely independent and previously uncharacterized roles in promoting NSC multilineage potential and modulating early neural fate decisions.

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Available from: Solen Gokhan, May 16, 2014
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    • "This hypothesis is reinforced by RNA-seq data showing that VEGF-C stimulation shifts NSCs from their undifferentiated state toward a proliferating progenitor state. VEGF-C/VEGFR3 signaling in NSCs downregulates the expression of Bmi-1 and Rest, which interact with a broad array of transcriptional and epigenetic regulatory cofactors to maintain stemness and inhibit NSC differentiation (Abrajano et al., 2010; Fasano et al., 2009). This suggests that activation of VEGFR3 by VEGF-C de-represses the NSC differentiation program. "
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    ABSTRACT: Neural stem cells (NSCs) continuously produce new neurons within the adult mammalian hippocampus. NSCs are typically quiescent but activated to self-renew or differentiate into neural progenitor cells. The molecular mechanisms of NSC activation remain poorly understood. Here, we show that adult hippocampal NSCs express vascular endothelial growth factor receptor (VEGFR) 3 and its ligand VEGF-C, which activates quiescent NSCs to enter the cell cycle and generate progenitor cells. Hippocampal NSC activation and neurogenesis are impaired by conditional deletion of Vegfr3 in NSCs. Functionally, this is associated with compromised NSC activation in response to VEGF-C and physical activity. In NSCs derived from human embryonic stem cells (hESCs), VEGF-C/VEGFR3 mediates intracellular activation of AKT and ERK pathways that control cell fate and proliferation. These findings identify VEGF-C/VEGFR3 signaling as a specific regulator of NSC activation and neurogenesis in mammals. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Cell Reports 02/2015; 10(7). DOI:10.1016/j.celrep.2015.01.049 · 8.36 Impact Factor
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    • "Consistent with BioGPS analysis (Figure 4), a majority of the 62 non-neural cell lines used for acquisition of the ENCODE TF ChIP-seq data (Figure 6 and Additional file 5) exhibit a single highly occupied site in the PGBD5 promoter for NRSF/REST, a factor which serves as a scaffold for assembly of many other proteins that can repress neural genes in non-neural cells [43]. For example, the N-terminal domain of NRSF/REST binds the SIN3A co-repressor, which in turn binds the repressive HDAC1/2 (histone deacetylases 1 and 2) and STAT3, thereby acting as a context-dependent ISGF3/STAT3 transcriptional switch [44]; the C-terminal domain of NRSF/REST binds the CoREST co-repressor which not only binds HDAC1/2, but also the repressive DNMT1 (DNA methyltransferase 1), histone K4 demethylase, and histone K9 methyltransferase, thereby regulating gene networks that control neural stem cell fate decisions [45]; and the internal domain of NRSF/REST binds a family of DNA motifs that regulate neuronal gene networks [46]. Thus, binding of NRSF/REST to the CpG island in non-neural cells is likely to explain not only colocalization of HDAC2 but also the Ini1, BRG1, and BAF155 components of the SWI/SNF chromatin remodeling complex required for repression of neuronal genes by the C-terminal CoREST corepressor [47]. "
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    • "Therefore, the simultaneous suppression of miR-9 and miR-9* may be expected to result in derepression of the REST/coREST complex and, consequently, inhibition of neuronal differentiation. On the other hand, preferential suppression of either miR-9 or miR-9* would be predicted to alter the ratio of REST to coREST, which has important and complex consequences for neural stem-cell renewal and altered lineage specification (Abrajano et al. 2009, 2010). Clearly, the involvement of passenger-strand miRNA biology in teratogenesis needs further investigation. "
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