Transcriptional repression by neuron-restrictive silencer factor is mediated via the Sin3-histone deacetylase complex.
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.
Roopra
A
A
Wellcome Laboratory for Molecular Pharmacology, University College London, London WC1E 6BT, United Kingdom. aroopra@hgmp.mrc.ac.uk
Sharling
L
L
Wood
I C
IC
Briggs
T
T
Bachfischer
U
U
Paquette
A J
AJ
Buckley
N J
NJ
D002460:Cell Line; D005786:Gene Expression Regulation; D006655:Histone Deacetylases / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D009474:Neurons / Q000502:physiology*; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins; D015398:Signal Transduction / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic; D000099229:RE1-Silencing Transcription Factor
D006655:Histone Deacetylases; D012097:Repressor Proteins; D029701:Saccharomyces cerevisiae Proteins; D014157:Transcription Factors; D000099229:RE1-Silencing Transcription Factor; C071731:SIN3 protein, S cerevisiae