Novel mechanism of positive versus negative regulation by thyroid hormone receptor beta 1 (TRß1) identified by genome-wide profiling of binding sites in mouse liver

Triiodothyronine (T3) regulates key metabolic processes in the liver through the thyroid hormone receptor, TRß1. However, the number of known target-genes directly regulated by TRß1 is limited, and the mechanisms by which positive and especially negative transcriptional regulation occur are not well understood. To characterize the TRß1 cistrome in vivo, we expressed a biotinylated TRß1 in hypo and hyperthyroid mouse livers and used ChIP-seq to identify genomic TRß1 targets, and correlated this data with gene expression changes. As with other nuclear receptors, the majority of TRß1 binding sites were not in proximal promoters, but in the gene body of known genes. Remarkably, T3 can dictate changes in TRß1 binding, with strong correlation to T3-induced gene expression changes, suggesting that differential TRß1 binding regulates transcriptional outcome. Additionally, DR-4 and DR-0 motifs were significantly enriched at binding sites where T3 induced an increase or decrease in TRß1 binding respectively, leading to either positive or negative regulation by T3. Taken together this study provides new insights into the mechanisms of transcriptional regulation by TRß1 in vivo.