The Basic Helix-Loop-Helix Protein, SHARP-1, Represses Transcription by a Histone Deacetylase-dependent and Histone Deacetylase-independent Mechanism

• Published in: The Journal of biological chemistry 2001-05, Vol.276 (18), p.14821-14828
• Main Authors: Garriga-Canut, Mireia, Roopra, Avtar, Buckley, Noel.J.
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Base Sequence; Basic Helix-Loop-Helix Transcription Factors; Cell Line; DNA Primers; Helix-Loop-Helix Motifs; Helix-loop-helix proteins (basic); Histone Deacetylases - metabolism; Molecular Sequence Data; Neuropeptides - chemistry; Neuropeptides - physiology; Repressor Proteins - physiology; Sequence Homology, Amino Acid; SHARP-1 protein; Transcription Factors - chemistry; Transcription Factors - physiology; Transcription, Genetic - physiology
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M011619200

Many aspects of neurogenesis and neuronal differentiation are controlled by basic helix-loop-helix (bHLH) proteins. One such factor is SHARP-1, initially identified on the basis of its sequence similarity to hairy. Unlikehairy, and atypically for bHLHs, SHARP-1 is expressed late in development, suggestive of a role in terminal aspects of differentiation. Nevertheless, the role of SHARP-1 and the identity of its target genes remain unknown. During the course of a one-hybrid screen for transcription factors that bind to regulatory domains of the M1 muscarinic acetylcholine receptor gene, we isolated the bHLH transcription factor SHARP-1. In this study, we investigated the functional role of SHARP-1 in regulating transcription. Fusion proteins of SHARP-1 tethered to the gal4 DNA binding domain repress both basal and activated transcription when recruited to either a TATA-containing or a TATAless promoter. Furthermore, we identified two independent repression domains 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, overexpression of SHARP-1 represses transcription from the M1 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.