Novel Mechanism of Positive versus Negative Regulation by Thyroid Hormone Receptor β1 (TRβ1) Identified by Genome-wide Profiling of Binding Sites in Mouse Liver

Background: Examining the TR1 cistrome in mouse liver is critical to understanding thyroid hormone signaling. Results: Novel mechanisms of positive versus negative regulation by biotinylated TR1 were identified. Conclusion: TR1 regulates transcription by changes in relative binding and use of preferred binding motifs. Significance: This study demonstrates that a mechanism other than differential co-regulator recruitment is involved in transcriptional regulation by TR1 Triiodothyronine (T3) regulates key metabolic processes in the liver through the thyroid hormone receptor, TR1. However, the number of known target genes directly regulated by TR1 is limited, and the mechanisms by which positive and especially negative transcriptional regulation occur are not well understood. To characterize the TR1 cistrome in vivo, we expressed a biotinylated TR1 in hypo- and hyperthyroid mouse livers, used ChIP-seq to identify genomic TR1 targets, and correlated these data with gene expression changes. As with other nuclear receptors, the majority of TR1 binding sites were not in proximal promoters but in the gene body of known genes. Remarkably, T3 can dictate changes in TR1 binding, with strong correlation to T3-induced gene expression changes, suggesting that differential TR1 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 TR1 binding, respectively, leading to either positive or negative regulation by T3. Taken together, the results of this study provide new insights into the mechanisms of transcriptional regulation by TR1 in vivo.