The basic helix-loop-helix protein, SHARP-1, represses transcription by a histone deacetylase-dependent and histone deacetylase-independent mechanism

Many aspects of neurogenesis and neuronal differentiation are controlled by basic helix-loop-helix (bHLH) proteins. One such factor is SHARP-1, initia lly identified on the basis of its sequence similarity to hairy. Unlike hai ry, and atypically for bHLHs, SHARP-1 is expressed late in development, sug gestive of a role in terminal aspects of differentiation. Nevertheless, the role of SHARP-1 and the identity of its target genes remain unknown. Durin g the course of a one-hybrid screen for transcription factors that bind to regulatory domains of the M-1 muscarinic acetylcholine receptor gene, we is olated the bHLH transcription factor SHARP-1. In this study, we investigate d the functional role of SHARP-1 in regulating transcription, Fusion protei ns of SHARP-1 tethered to the ga14 DNA binding domain repress both basal an d activated transcription when recruited to either a TATA-containing or a T ATAless promoter. Furthermore, we identified two independent repression dom ains that operate via distinct mechanisms. Repression by a domain in the C terminus is sensitive to the histone deacetylase inhibitor trichostatin A, whereas repression by the bHLH domain is insensitive to TSA Furthermore, ov erexpression of SHARP-1 represses transcription from the M-1 promoter. This study represents the first report to assign a function to, and to identify a target gene for, the bHLH transcription factor SHARP-1.