An investigaton of the mechanisms underlying N-CoR-mediated transcriptional repression of nuclear receptor-regulated genes

The precise regulation of protein-coding genes, by processes such as transcription, is essential for the survival of all complex organisms. Multiple proteins with varied functions are necessary to coordinate and strictly regulate transcription. Class II nuclear receptors (NRs) are ligand-induced transcription factors that are critical for development, tissue growth and differentiation, and metabolism. The primary function of NRs is to coordinate the ligand-induced exchange of large co-regulatory complexes that contain specific chromatin modifying enzymes. Hormones and vitamins, the ligands for NRs, thus play an important role in modulating their transcriptional activity. ^ The nuclear co-repressor (N-CoR) protein is essential for the transcriptional repression established by unliganded NRs. N-CoR contains transferable repressor domains which mediate transcriptional repression by associating with such proteins as histone deacetylases, histone-binding proteins, and DNA methyl CpG binding-proteins. N-CoR/SMRT acts, therefore, as a platform to coordinate the recruitment of multiple proteins with various activities, hence actively repressing transcription of a wide variety of genes. Multiple N-CoR complexes may exist to provide specificity for transcriptional repression within a given cell type or promoter as well as to allow N-CoR to be recruited by different transcription factors. Understanding the roles of co-regulatory proteins in the regulation of transcription by NRs will help explain the variation in the hormonal responsiveness of different genes. ^ In an attempt to isolate novel components of the N-CoR repression complex, human ATP-utilizing chromatin-assembly and -remodeling factor 1 (hAcf1) was identified as an N-CoR-interacting protein. hAcf1, a non-enzymatic member of a chromatin remodeling complex, plays key roles in the hormone responsiveness and in the transcriptional repression of specific class II NR-regulated genes. hAcf1 maintains the repressed promoter by stabilizing the co-repressor complex as well as the repressive local chromatin architecture. SUV39H1 was also isolated as a member of an N-CoR containing complex. The catalytic activity of this histone lysine methyltransferase (HMT) is required for N-CoR-mediated repression of NR-reporter genes. These results establish that hAcf1 and SUV39H1 are novel members of N-CoR complexes that are critical for the transcriptional repression of specific NR-regulated genes.