| Nuclear hormone receptors regulate diverse aspects of mammalian biology in response to the availability of small lipophillic signaling molecules. This is accomplished via modulation of the transcription of a variety of target genes. The switch from actively repressing transcription to activating transcription occurs through the exchange of NR associated cofactors. Repressive cofactors, such as SMRT, lead to recruitment of negative regulatory factors, including histone deacetylases, to NR target genes in the absence of ligand. Ligand stimulation results in the release of the SMRT associated corepressor complex and enables the recruitment of positive regulatory factors, including histone acetyltransferases.;SMRT is primarily thought to act as a platform protein, responsible for recruiting HDAC containing complexes to DNA bound TFs. We describe here an additional function of SMRT in activating the deacetylase activity of its associated complex. We attribute this function to the previously uncharacterized SANT domain and show that this function is specific to HDAC3.;SMRT is hypothesized to play a critical role in NR mediated repression and has been implicated in the pathologies of RTH and several types of leukemia. However, a productive model to determine the in vivo relevance of this relationship has not been established. In an effort to determine the in vivo significance of the interaction between SMRT and NRs, I have generated SMRT knock-in mouse lines harboring specific point mutations that disrupt NR interaction. These mice result in a variety of defects including reduced metabolism, growth retardation, and infertility. This provides the first genetic proof of the dependence of NR biology on appropriate corepressor interaction. |
