Transcription activation by the thyroid hormone receptor through ligand dependent receptor recruitment and chromatin remodeling. As a first step toward understanding how TR mutants act in vivo differently from the WT TR genome-wide, we first identified the cistrome of endogenous TRbeta1 and probed the chromatin landscape in the regulation of transcription by TR in the mouse liver. The current understanding of TR transcription regulation has been based on a bimodal switch model. In this model, the unliganded TR forms chromatin bound stable complexes with transcriptional co-repressors to repress transcription. Binding of T3 dissociates co-repressors and facilitates recruitment of co-activators to activate transcription. Using ChIP-seq against endogenous TRbeta1, we found that in addition to T3-independent TRbeta1 occupancy, there is considerable T3-induced TRbeta1 recruitment to chromatin associated with chromatin remodeling to activate gene transcription. DNase I hypersensitive site sequencing (DNase-seq) data provide little evidence for TRbeta1 footprints either in the absence or presence of T3. These results suggest the unliganded TR engagement with repressive complexes on chromatin, similar to activating receptor complexes, is a highly dynamic process. The action of TR now appears more aligned with well-developed models for steroid hormone receptor action. This new model of T3 action represents a significant step toward a better understanding of mechanisms of gene regulation by this important hormone. Importantly, the present work has facilitated the studies for gaining molecular insights into the basis of TR mutations in disease.
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