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Molecular and Cellular Biology, March 2000, p. 2147-2157, Vol. 20, No. 6
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

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

Avtar Roopra,1,2,* Lisa Sharling,1 Ian C. Wood,1,2 Teresa Briggs,1 Ulla Bachfischer,1 Alice J. Paquette,3 and Noel J. Buckley1,2

Wellcome Laboratory for Molecular Pharmacology, University College London, London WC1E 6BT,1 and School of Biochemistry and Molecular Biology, University of Leeds, Leeds LS2 9JT,2 United Kingdom, and Division of Biology, California Institute of Technology, Pasadena, California 911253

Received 25 October 1999/Accepted 6 December 1999

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.

* Corresponding author. Mailing address: School of Biochemistry and Molecular Biology, University of Leeds, Leeds LS2 9JT, United Kingdom. Phone: 44 113 233 3015. Fax: 113 233 3019. E-mail: aroopra{at}hgmp.mrc.ac.uk.

Molecular and Cellular Biology, March 2000, p. 2147-2157, Vol. 20, No. 6
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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