BIOLOGICAL-ACTIVITY AND MODULAR STRUCTURE OF RE-1-SILENCING TRANSCRIPTION FACTOR (REST), A REPRESSOR OF NEURONAL GENES

The zinc finger protein RE-1-silencing transcription factor (REST)(1) is a transcriptional repressor that represses neuronal genes in nonneu ronal tissues. Transfection experiments of neuroblastoma cells using a REST expression vector revealed that synapsin I promoter activity is controlled by REST. The biological activity of REST was further invest igated using a battery of model promoters containing strong promoters/ enhancers and REST binding sites. REST functioned as a transcriptional repressor when REST binding motifs derived from the genes encoding sy napsin I, SCG10, alpha(1)-glycine receptor, the beta 2-subunit of the neuronal nicotinic acetylcholine receptor, and the m4-subunit of the m uscarinic acetylcholine receptor were present in the promoter region. No differences in the biological activity of these REST binding motifs tested were detected. Moreover, we found that REST functioned very ef fectively as a transcriptional repressor at a distance. Thus, REST rep resents a general transcriptional repressor that blocks transcription regardless of the location or orientation of its binding site relative to the enhancer and promoter. This biological activity could also be attributed to isolated domains of REST. Both repressor domains identif ied at the N and C termini of REST were transferable to a heterologous DNA binding domain and functioned from proximal and distal positions, similar to the REST protein.