Small CTD Phosphatases Function in Silencing Neuronal Gene Expression

Yeo, Michele; Lee, Soo Kyung; Lee, Bora; Ruiz, Esmeralda C.; Pfaff, Samuel L.; Gill, Gordon N.

doi:10.1126/science.1100801

Cited by 205 publications

(226 citation statements)

References 28 publications

(6 reference statements)

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“…CTDSP1 was first identified as a phosphatase for the C-terminal domain of RNA polymerase II in vitro (34). The expression of CTDSP1 decreases dramatically with differentiation of stem cells to mature neurons (33), and knockdown of CTDSP1 in a neural progenitor cell line accelerates neuronal differentiation (22). These results led to the hypothesis that REST recruits CTDSP1 to the RNA polymerase II initiation complex where it specifically dephosphorylates Pol II CTD to attenuate transcription (22,33).…”

Section: Discussionmentioning

confidence: 99%

“…Although REST has been observed in some cellular contexts in the cytoplasm (28,31,32), its half-life in this cell compartment has not been measured, and whether its cytoplasmic complexes contain kinases or phosphatases has not been determined. In contrast, REST has been detected, together with a phosphatase, CTDSP1, on neuronal gene chromatin (33). CTDSP1 was first identified as a phosphatase for the C-terminal domain of RNA polymerase II in vitro (34).…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

C-terminal domain small phosphatase 1 and MAP kinase reciprocally control REST stability and neuronal differentiation

Nesti

Corson

McCleskey

et al. 2014

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

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The repressor element 1 (RE1) silencing transcription factor (REST) in stem cells represses hundreds of genes essential to neuronal function. During neurogenesis, REST is degraded in neural progenitors to promote subsequent elaboration of a mature neuronal phenotype. Prior studies indicate that part of the degradation mechanism involves phosphorylation of two sites in the C terminus of REST that require activity of beta-transducin repeat containing E3 ubiquitin protein ligase, βTrCP. We identify a proline-directed phosphorylation motif, at serines 861/864 upstream of these sites, which is a substrate for the peptidylprolyl cis/trans isomerase, Pin1, as well as the ERK1/2 kinases. Mutation at S861/864 stabilizes REST, as does inhibition of Pin1 activity. Interestingly, we find that C-terminal domain small phosphatase 1 (CTDSP1), which is recruited by REST to neuronal genes, is present in REST immunocomplexes, dephosphorylates S861/864, and stabilizes REST. Expression of a REST peptide containing S861/864 in neural progenitors inhibits terminal neuronal differentiation. Together with previous work indicating that both REST and CTDSP1 are expressed to high levels in stem cells and down-regulated during neurogenesis, our results suggest that CTDSP1 activity stabilizes REST in stem cells and that ERK-dependent phosphorylation combined with Pin1 activity promotes REST degradation in neural progenitors.T he repressor element 1 (RE1) silencing transcription factor (REST) is a transcriptional repressor that suppresses neuronal gene expression in nonneural cells, such as fibroblasts, as well as in neural progenitors (1-3). Its targets represent genes required for the terminally differentiated neuronal cell phenotype, including genes encoding voltage and ligand-dependent ion channels, receptors, growth factors, and axonal-guidance proteins (4-7). Thus, during neurogenesis, REST is progressively down-regulated to allow elaboration of the mature neuronal phenotype (3). Nonetheless, precisely how REST itself is regulated still remains an open question. Relatively little is known about either its transcriptional or posttranscriptional regulation (3,8,9). In contrast, several studies have focused on posttranslational regulation of REST (3, 10, 11), but the identity of the signaling molecules involved has received little attention.In neural progenitors and human embryonic kidney (HEK) cells, rapid REST turnover is mediated by targeting to a proteasomal pathway (3, 10, 11). REST degradation during neuronal differentiation in culture requires interaction with beta-transducin repeat containing E3 ubiquitin protein ligase (βTrCP) for targeting to the proteasome (11). βTrCP was also required for cell-cycle-dependent degradation of REST in HEK cells (10). Two adjacent phosphorylated peptides in the C-terminal domain of REST were identified as βTrCP substrates in these studies, and function as degrons. One kinase responsible for the phosphorylation and degron activity in hippocampus is casein kinase 1, CK1 (12), but whether it function...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

C-terminal domain small phosphatase 1 and MAP kinase reciprocally control REST stability and neuronal differentiation

Nesti

Corson

McCleskey

et al. 2014

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

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“…55 SCP1 is an antineural factor that acts as a part of the REST complex to prevent the expression of neural genes in nonneural tissues. 56 This results in the establishment of a double-negative feedback loop between miR-124 and the REST complex. Thus, microRNA-124-regulated circuitry is emerging in which it plays a central role in neural differentiation.…”

Section: Micrornas In Glioblastomamentioning

confidence: 99%

MicroRNAs and glioblastoma; the stem cell connection

et al. 2009

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Recent data draw close parallels between cancer, including glial brain tumors, and the biology of stem and progenitor cells. At the same time, it has become clear that one of the major roles that microRNAs play is in the regulation of stem cell biology, differentiation, and cell 'identity'. For example, microRNAs have been increasingly implicated in the regulation of neural differentiation. Interestingly, initial studies in the incurable brain tumor glioblastoma multiforme strongly suggest that microRNAs involved in neural development play a role in this disease. This encourages the idea that certain miRs allow continued tumor growth through the suppression of differentiation and the maintenance of the stem cell-like properties of tumor cells. These concepts will be explored in this article.

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“…The elements reside in genes central to neurogenesis, including ion channels, neurotransmitter receptors, axonal guidance molecules, and the neurogenic gene NeuroD . REST/NRSF imposes dynamic, impermanent repression through its association with the corepressors CTD phosphatase, which inhibits RNA polymerase II, and HDACs, which limit chromatin accessibility (Battaglioli et al, 2002;Yeo et al, 2005). The corepressor Co-REST coordinates stable, epigenetic repression by directly binding the H3K9 HMT G9a and the H3K4 demethylase LSD1 (Roopra et al, 2004;Shi et al, 2004).…”

Section: Lineage Restriction Rest/nrsf Activities Govern Neuronal Fatmentioning

confidence: 99%

Epigenetics in development

Kiefer

2007

Developmental Dynamics

237

144

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It has become increasingly evident in recent years that development is under epigenetic control. Epigenetics is the study of heritable changes in gene function that occur independently of alterations to primary DNA sequence. The best-studied epigenetic modifications are DNA methylation, and changes in chromatin structure by histone modifications, and histone exchange. An exciting, new chapter in the field is the finding that long-distance chromosomal interactions also modify gene expression. Epigenetic modifications are key regulators of important developmental events, including X-inactivation, genomic imprinting, patterning by Hox genes and neuronal development. This primer covers these aspects of epigenetics in brief, and features an interview with two epigenetic scientists. Developmental Dynamics 236: 1144 -1156, 2007.

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Small CTD Phosphatases Function in Silencing Neuronal Gene Expression

Cited by 205 publications

References 28 publications

C-terminal domain small phosphatase 1 and MAP kinase reciprocally control REST stability and neuronal differentiation

C-terminal domain small phosphatase 1 and MAP kinase reciprocally control REST stability and neuronal differentiation

MicroRNAs and glioblastoma; the stem cell connection

Epigenetics in development

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