Article

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: 9.81). 09/2010; 107(38):16685-90. DOI: 10.1073/pnas.0906917107
Source: PubMed

ABSTRACT 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.

Download full-text

Full-text

Available from: Solen Gokhan, May 16, 2014
1 Follower
 · 
79 Views
  • Source
    • "In addition, there are reports that the Cyc8–Tup1 complex can function as a transcriptional coactivator for genes like GRE2, AHP1, ARG1, FET3, and ARN1 (Proft and Struhl 2002; Kim et al. 2005; Crisp et al. 2006). The dual functionality seen for Tup1 also has been observed for other transcriptional regulators, such as Myc and REST/ CoREST (Ballas and Mandel 2005; Eilers and Eisenman 2008; Abrajano et al. 2010). These transcriptional regulators can interact with multiple transcriptional regulatory proteins and assemble diverse complexes that function as either an activator or a repressor in a context-dependent manner. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Transcriptional activity of a gene is governed by transcriptional regulatory complexes that assemble/disassemble on the gene and control the chromatin architecture. How cytoplasmic components influence the assembly/disassembly of transcriptional regulatory complexes is poorly understood. Here we report that the budding yeast Saccharomyces cerevisiae has a chromatin architecture-modulating mechanism that is dependent on the endosomal lipid PI(3,5)P(2). We identified Tup1 and Cti6 as new, highly specific PI(3,5)P(2) interactors. Tup1--which associates with multiple transcriptional regulators, including the HDAC (histone deacetylase) and SAGA complexes--plays a crucial role in determining an activated or repressed chromatin state of numerous genes, including GAL1. We show that, in the context that the Gal4 activation pathway is compromised, PI(3,5)P(2) plays an essential role in converting the Tup1-driven repressed chromatin structure into a SAGA-containing activated chromatin structure at the GAL1 promoter. Biochemical and cell biological experiments suggest that PI(3,5)P(2) recruits Cti6 and the Cyc8-Tup1 corepressor complex to the late endosomal/vacuolar membrane and mediates the assembly of a Cti6-Cyc8-Tup1 coactivator complex that functions to recruit the SAGA complex to the GAL1 promoter. Our findings provide important insights toward understanding how the chromatin architecture and epigenetic status of a gene are regulated by cytoplasmic components.
    Genes & development 05/2011; 25(9):984-95. DOI:10.1101/gad.1998611 · 12.64 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Complementary transcriptional and epigenetic regulatory factors (e.g., histone and chromatin modifying enzymes and non-coding RNAs) regulate genes responsible for mediating neural stem cell maintenance and lineage restriction, neuronal and glial lineage specification, and progressive stages of lineage maturation. However, an overall understanding of the mechanisms that sense and integrate developmental signals at the genomic level and control cell type-specific gene network deployment has not emerged. REST and CoREST are central players in the transcriptional and epigenetic regulatory circuitry that is responsible for modulating neural genes, and they have been implicated in establishing cell identity and function, both within the nervous system and beyond it. Herein, we discuss the emerging context-specific roles of REST and CoREST and highlight our recent studies aimed at elucidating their neural developmental cell type- and stage-specific actions. These observations support the conclusion that REST and CoREST act as master regulators of key neural cell fate decisions.
    Cell cycle (Georgetown, Tex.) 11/2010; 9(22):4477-86. DOI:10.4161/cc.9.22.13973 · 5.01 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The development of a neuron from a precursor cell comprises a complex set of steps ranging from regulation of the proliferative cycle through the acquisition of distinct morphology and functionality. How these processes are orchestrated is largely unknown. Using in utero manipulation of gene expression in the mouse embryonic cerebral cortex, we found that the transition between multipolar and bipolar stages of newborn cortical pyramidal neurons is markedly delayed by depletion of CoREST, a corepressor component of chromatin remodeling complexes. This profoundly affects the onset of their radial migration. The loss of CoREST function also perturbs the dynamics of neuronal precursor cell populations, transiently increasing the fraction of cells remaining in progenitor states, but not the acquisition of the neuronal glutamatergic fate of pyramidal cells. The function of CoREST in these processes appears to be independent of its best-known interactor, the RE-1 silencer of transcription/neural restrictive silencing factor, and requires the histone demethylase LSD1. This reveals the importance of epigenetic control in the execution of neural development programs, specifically in the cerebral cortex.
    Cerebral Cortex 08/2011; 22(6):1431-41. DOI:10.1093/cercor/bhr218 · 8.67 Impact Factor
Show more