The functional relationship between corepressor N‐CoR and SMRT in mediating transcriptional repression by thyroid hormone receptor alpha

Abstract

A central issue in mediating repression by nuclear hormone receptors is the distinct or redundant function between corepressors N-CoR and SMRT. To address the functional relationship between SMRT and N-CoR in TR-mediated repression, we have identified multiple TR-target genes, including BCL3 (B-Cell Lymphoma 3-encoded protein), Spot14 (thyroid hormone-inducible hepatic protein), FAS (fatty acid synthase), and ADRB2 (beta-adrenergic receptor). We demonstrated that siRNA treatment against either NCoR or SMRT is sufficient for the derepression of multiple TR-target genes. By the combination of sequence mining and physical association as determined by chromatin immunoprecipitation (ChIP) assays, we mapped the putative TREs (TR binding sites) in BCL3, Spot14, FASN, and ADRB2 genes. Our data clearly shows that the SMRT and N-CoR are independently recruited to various TR target genes. We also present evidence that overexpression of N-CoR can restore repression of endogenous genes after knocking-down SMRT. Finally, unliganded, corepressor-free TR is defective in repression and interacts with coactivator, p300. Collectively, these results suggest that both SMRT and N-CoR are limited in cells and that knocking down either of them results in corepressor-free TR and consequently derepression of TR target genes. This work was supported by the Korea Science and Engineering Foundation (KOSEF) grant funded by the Korea gorvenment (MOST) (No. R13-2002-054-04002-0) & (KOSEF 2007-8-1158)