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Transcriptional Repression by Neuron-Restrictive Silencer Factor Is Mediated via the Sin3-Histone Deacetylase Complex

Roopra, Avtar and Sharling, Lisa and Wood, Ian C. and Briggs, Teresa and Bachfischer, Ulla and Paquette, Alice J. and Buckley, Noel J. (2000) Transcriptional Repression by Neuron-Restrictive Silencer Factor Is Mediated via the Sin3-Histone Deacetylase Complex. Molecular and Cellular Biology, 20 (6). pp. 2147-2157. ISSN 0270-7306. http://resolver.caltech.edu/CaltechAUTHORS:ROOmcb00

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Abstract

A large number of neuron-specific genes characterized to date are under the control of negative transcriptional regulation. Many promoter regions of neuron-specific genes possess the repressor element repressor element 1/neuron-restrictive silencing element (RE1/NRSE). Its cognate binding protein, REST/NRSF, is an essential transcription factor; its null mutations result in embryonic lethality, and its dominant negative mutants produce aberrant expression of neuron-specific genes. REST/NRSF acts as a regulator of neuron-specific gene expression in both nonneuronal tissue and developing neurons. Here, we shown that heterologous expression of REST/NRSF in Saccharomyces cerevisiae is able to repress transcription from yeast promoters engineered to contain RE1/NRSEs. Moreover, we have taken advantage of this observation to show that this repression requires both yeast Sin3p and Rpd3p and that REST/NRSF physically interacts with the product of the yeast SIN3 gene in vivo. Furthermore, we show that REST/NRSF binds mammalian SIN3A and HDAC-2 and requires histone deacetylase activity to repress neuronal gene transcription in both nonneuronal and neuronal cell lines. We show that REST/NRSF binding to RE1/NRSE is accompanied by a decrease in the acetylation of histones around RE1/NRSE and that this decrease requires the N-terminal Sin3p binding domain of REST/NRSF. Taken together, these data suggest that REST/NRSF represses neuronal gene transcription by recruiting the SIN3/HDAC complex.


Item Type:Article
Additional Information:Copyright © 2000, American Society for Microbiology. Received 25 October 1999/Accepted 6 December 1999 We are indebted to the lab of Mark Johnston, Washington University, St. Louis, Mo., for plasmid pBM2389 and invaluable guidance throughout the course of the yeast work. We thank Luigi Lania, IIGB, Naples, Italy, for the T7G5TATA reporter plasmid. Plasmid pSKD7 containing the NaII promoter region was a generous gift from Gail Mandel, Stony Brook, N.Y. We thank Mireia Garriga-Canut for construction of pGL3.Inr, Helene Marie for construction of pLEONOV.NRSF(139-600), Francesca Caccuci and Richard Rowe for their contributions, and Martin Raff, University College London, London, United Kingdom, for critical reading of the manuscript. This work was supported by the Wellcome Trust and by NIH grant NS23476 to David Anderson, Howard Hughes Medical Institute, California Institute of Technology. A.R. is the recipient of a Wellcome Prize Fellowship, and A.J.P. is supported by an NIH predoctoral training grant.
Record Number:CaltechAUTHORS:ROOmcb00
Persistent URL:http://resolver.caltech.edu/CaltechAUTHORS:ROOmcb00
Alternative URL:http://mcb.asm.org/cgi/content/abstract/20/6/2147
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ID Code:3442
Collection:CaltechAUTHORS
Deposited By: Archive Administrator
Deposited On:07 Jun 2006
Last Modified:26 Dec 2012 08:54

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