REST and CoREST are transcriptional and epigenetic regulators of seminal neural fate decisions

Qureshi, Irfan A.; Gökhan, Şölen; Mehler, Mark F.

doi:10.4161/cc.9.22.13973

Cited by 126 publications

(110 citation statements)

References 115 publications

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“…There, it recruits a broad array of epigenetic and transcriptional modulators, often with the assistance of scaffold proteins, such as CoREST (also known as Rcor1) (Gopalakrishnan, 2009;Qureshi et al, 2010). REST is itself transcriptionally and posttranscriptionally modulated (Ballas et al, 2005;Westbrook et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

P120-catenin regulates REST/CoREST, and modulates mouse embryonic stem cell differentiation

Lee

Furuta

et al. 2014

Journal of Cell Science

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Although the canonical Wnt pathway and b-catenin have been extensively studied, less is known about the role of p120-catenin (also known as d1-catenin) in the nuclear compartment. Here, we report that p120-catenin binds and negatively regulates REST and CoREST (also known as Rcor1), a repressive transcriptional complex that has diverse developmental and pathological roles. Using mouse embryonic stem cells (mESCs), mammalian cell lines, Xenopus embryos and in vitro systems, we find that p120-catenin directly binds the REST-CoREST complex, displacing it from established gene targets to permit their transcriptional activation. Importantly, p120-catenin levels further modulate the mRNA and protein levels of Oct4 (also known as POU5F1), Nanog and Sox2, and have an impact upon the differentiation of mESCs towards neural fates. In assessing potential upstream inputs to this new p120-catenin-REST-CoREST pathway, REST gene targets were found to respond to the level of E-cadherin, with evidence suggesting that p120-catenin transduces signals between Ecadherin and the nucleus. In summary, we provide the first evidence for a direct upstream modulator and/or pathway regulating REST-CoREST, and reveal a substantial role for p120-catenin in the modulation of stem cell differentiation.

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Section: Introductionmentioning

confidence: 99%

P120-catenin regulates REST/CoREST, and modulates mouse embryonic stem cell differentiation

Lee

Furuta

et al. 2014

Journal of Cell Science

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“…For example, a protein whose importance in epigenetic regulation of neural genes has been recognized is RE1 Silencing Transcription factor (REST) Corepressor 1 (RCOR1) (1, reviewed in ref. 2). RCOR1 was identified originally as a direct binding partner for the master transcriptional regulator of neural genes, REST (3)(4)(5).…”

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confidence: 99%

“…Furthermore, RCOR2 is recruited by some of the same RCOR1-associated transcription factors, including REST, GFI1B, and ZMYND8 (15,16). Despite knowledge of their cell-specific roles in some contexts (2,17), the importance of RCOR1/2 in brain development has yet to be established definitively.…”

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confidence: 99%

REST corepressors RCOR1 and RCOR2 and the repressor INSM1 regulate the proliferation–differentiation balance in the developing brain

Monaghan

Nechiporuk

Jeng

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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The transcriptional events that lead to the cessation of neural proliferation, and therefore enable the production of proper numbers of differentiated neurons and glia, are still largely uncharacterized. Here, we report that the transcription factor Insulinoma-associated 1 (INSM1) forms complexes with RE1 Silencing Transcription factor (REST) corepressors RCOR1 and RCOR2 in progenitors in embryonic mouse brain. Mice lacking both RCOR1 and RCOR2 in developing brain die perinatally and generate an abnormally high number of neural progenitors at the expense of differentiated neurons and oligodendrocyte precursor cells. In addition, Rcor1/2 deletion detrimentally affects complex morphological processes such as closure of the interganglionic sulcus. We find that INSM1, a transcription factor that induces cell-cycle arrest, is coexpressed with RCOR1/2 in a subset of neural progenitors and forms complexes with RCOR1/2 in embryonic brain. Further, the Insm1 −/− mouse phenocopies predominant brain phenotypes of the Rcor1/2 knockout. A large number of genes are concordantly misregulated in both knockout genotypes, and a majority of the down-regulated genes are targets of REST. Rest transcripts are up-regulated in both knockouts, and reducing transcripts to control levels in the Rcor1/2 knockout partially rescues the defect in interganglionic sulcus closure. Our findings indicate that an INSM1/RCOR1/2 complex controls the balance of proliferation and differentiation during brain development.he development of the nervous system is an intricately orchestrated series of events beginning with formation of neuroepithelia. Progenitors that emerge from neuroepithelial stem cells undergo several proliferative transitions before ceasing to divide and terminally differentiating into neurons and glia. Both maintenance of the proliferative state and terminal transition to differentiated neurons and glia are regulated, in part, by chromatin-modifying proteins that are recruited to genes by specific transcription factors. In many cases, however, chromatin-modifying proteins have only been studied in vitro, and their roles in vivo remain unknown. For example, a protein whose importance in epigenetic regulation of neural genes has been recognized is RE1 Silencing Transcription factor (REST) Corepressor 1 (RCOR1) (1, reviewed in ref. 2). RCOR1 was identified originally as a direct binding partner for the master transcriptional regulator of neural genes, REST (3-5). The REST/RCOR1 complex has been studied primarily in cultured stem/progenitor cells, neurons, and glia (6-9). Like many other adaptor proteins in transcriptional complexes, RCOR1 does not have intrinsic enzymatic activity but rather binds directly to chromatin-modifying enzymes including histone deacetylases 1 and 2 (HDAC1/2) and the histone demethylase KDM1A (LSD1) (10-12). A related protein, RCOR2, shares ∼90% homology with RCOR1 in the ELM2 and SANT functional domains (13) and is also found in complexes with KDM1A and HDAC1/2 (14). Furthermore, RCOR2 is recruited by some of t...

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“…play a functionally conserved role in neurogenesis (Andres et al, 1999;Tontsch et al, 2001;de la Calle-Mustienes et al, 2002;Jarriault and Greenwald, 2002;Dallman et al, 2004). Recent studies show that CoREST regulates a very broad range of genes by both REST-dependent and REST-independent means, including genes encoding members of key neural developmental signaling pathways, such as BMP, SHH, Notch, RA, FGF, EGF and WNT (Abrajano et al, 2009a;Abrajano et al, 2010;Qureshi et al, 2010). Analysis of CoREST downstream target genes and their developmental expression profiles suggested that the liberation of CoREST from gene promoters is associated with both gene repression and activation depending on the cell context (Abrajano et al, 2009a;Abrajano et al, 2009b;Abrajano et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

“…Mammalian CoREST acts as a scaffold for recruitment of transcriptional regulators such as REST, and epigenetic factors such as the enzymes HDAC1, HDAC2 and LSD1 (Lakowski et al, 2006;Qureshi et al, 2010). In Drosophila, using two-hybrid interaction, CoREST was also shown to interact with Su(VAR)3-3 (Drosophila homolog of LSD1) and Rpd3 (HDAC1) (Dallman et al, 2004).…”

Section: Transcriptional and Epigenetic Functions Of Corestmentioning

confidence: 99%

CoREST acts as a positive regulator of Notch signaling in the follicle cells ofDrosophila melanogaster

Domanitskaya

Schüpbach

2012

Journal of Cell Science

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The Notch signaling pathway plays important roles in a variety of developmental events. The context-dependent activities of positive and negative modulators dramatically increase the diversity of cellular responses to Notch signaling. In a screen for mutations affecting the Drosophila melanogaster follicular epithelium, we isolated a mutation in CoREST that disrupts the Notch-dependent mitotic-to-endocycle switch of follicle cells at stage 6 of oogenesis. We show that Drosophila CoREST positively regulates Notch signaling, acting downstream of the proteolytic cleavage of Notch but upstream of Hindsight activity; the Hindsight gene is a Notch target that coordinates responses in the follicle cells. We show that CoREST genetically interacts with components of the Notch repressor complex, Hairless, C-terminal Binding Protein and Groucho. In addition, we demonstrate that levels of H3K27me3 and H4K16 acetylation are dramatically increased in CoREST mutant follicle cells. Our data indicate that CoREST acts as a positive modulator of the Notch pathway in the follicular epithelium as well as in wing tissue, and suggests a previously unidentified role for CoREST in the regulation of Notch signaling. Given its high degree of conservation among species, CoREST probably also functions as a regulator of Notch-dependent cellular events in other organisms.

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REST and CoREST are transcriptional and epigenetic regulators of seminal neural fate decisions

Cited by 126 publications

References 115 publications

P120-catenin regulates REST/CoREST, and modulates mouse embryonic stem cell differentiation

P120-catenin regulates REST/CoREST, and modulates mouse embryonic stem cell differentiation

REST corepressors RCOR1 and RCOR2 and the repressor INSM1 regulate the proliferation–differentiation balance in the developing brain

CoREST acts as a positive regulator of Notch signaling in the follicle cells ofDrosophila melanogaster

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