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 n euron-specific genes possess the repressor element repressor element 1/neur on-restrictive silencing element (RE1/NRSE). Its cognate binding protein, R EST/NRSF, is an essential transcription factor; its null mutations result i n embryonic Lethality, and its dominant negative mutants produce aberrant e xpression 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 engineere d to contain RE1/NRSEs, Moreover, we have taken advantage of this observati on to show that this repression requires both yeast Sin3p and Rpd3p and tha t 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 transcr iption 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 hist ones around RE1/NRSE and that this decrease requires the N-terminal Sin3p b inding domain of REST/NRSF. Taken together, these data suggest that REST/NR SF represses neuronal gene transcription by recruiting the SIN3/HDAC comple x.