Mechanisms of repression by nuclear receptor corepressors

Nuclear hormone receptors constitute a family of transcription factors that plays a critical role in development, differentiation, and homeostasis, regulating gene expression through both activation and repression. Progress in the study of nuclear receptor repression has increased dramatically in the past five years, beginning with the isolation of the two associated corepressor molecules, N-CoR and SMRT. Initial studies linked corepressor function to the recruitment of mSin3 complexes and ascribed the histone deacetylase activity of N-CoR and SMRT to HDAC1. Surprisingly, however, numerous biochemical studies have not detected N-CoR or SMRT in mSin3- and HDAC1-containing complexes. The objective of this work was to characterize the functions of the multiple, non-redundant repression domains of these corepressors and investigate their mechanisms of action. We identified a novel protein, called NAP1, which may mediate repression by a specific repression domain of N-CoR. We showed that a separate repression domain, which is conserved in N-CoR and SMRT, represses transcription by interacting directly with the class II deacetylases HDAC4 and HDAC5 in a complex that does not contain mSin3A or HDAC1. Our work also examined the role of the nuclear receptor TR in corepressor complex formation. These studies suggest that corepressor complex formation may be regulated by signals which determine component (HDAC) availability, and that the corepressor complex itself may differ depending upon the presence of particular nuclear receptors.