Transcriptional repression by thyroid hormone receptors - A role for receptor homodimers in the recruitment of SMRT corepressor

Nuclear hormone receptors, such as the thyroid hormone receptors (T3Rs) and retinoid X receptors (RXRs), are ligand-regulated transcription factors th at control key aspects of metazoan gene expression. T3Rs can bind to DNA ei ther as receptor homodimers or as heterodimers with RXRs, Once bound to DNA , nuclear hormone receptors regulate target gene expression by recruiting a uxiliary proteins, denoted corepressors and coactivators, We report here th at T3R homodimers assembled on DNA exhibit particularly strong interactions with the SMRT corepressor, whereas T3R.RXR heterodimers are inefficient at binding to SMRT, Mutants of T3R that exhibit enhanced repression propertie s, such as the v-Erb A oncoprotein or the T3R beta-Delta 432 mutant found i n human resistance to thyroid hormone syndrome, display enhanced homodimeri zation properties and exhibit unusually strong interactions with the SMRT c orepressor. Significantly, the topology of a DNA binding site can determine whether that site recruits primarily homodimers or heterodimers and theref ore whether corepressor is efficiently or inefficiently recruited to the re sulting receptor-DNA complex. We suggest that T3R homodimers, and not heter odimers, may be important mediators of transcriptional repression and that the nature of the DNA binding site, by selecting for receptor homodimers or heterodimers, can influence the ability of the receptor to recruit corepre ssor.