Transcriptional repression by a core nuclear hormone receptor corepressor complex

The SMRT and N-CoR corepressors, mediate transcriptional repression by unliganded nuclear hormone receptors and other classes of transcription factors including PLZF, RBP-Jk/CBF1, Pit-1, Rpx2, Pbx, BCL6, MyoD and SMAD. In the present work, we describe the biochemical isolation of a core SMRT corepressor complex. This complex contains transducin β-like protein 1 (TBL1), whose gene is mutated in human sensorineural deafness. It also contains HDAC3, a histone deacetylase not previously thought to interact with SMRT. TBL1 displays structural and functional similarities to the yeast Sif2 telomere binding protein as well as the Tup1 and Groucho corepressors. In vivo, TBL1 is bridged to HDAC3 through SMRT and can potentiate repression by TR. We go on to show that the SMRT corepressor serves as an activating cofactor for HDAC3. The ability of this nuclear hormone receptor corepressor to activate the enzymatic activity of HDAC3 is provided by a SANT containing deacetylase activating domain (DAD) present within both SMRT and N-CoR. Furthermore, the ability of SMRT to recruit HDAC3 is necessary for its main repressive function. Finally, we show that SMRT can bind to the unacetylated amino terminal tails of histones H3 and H4. This work reveals the identity of a core SMRT corepressor complex, the mechanisms governing its histone deacetylase activity, and its linkage to chromatin structure