title: Novel mechanism of positive versus negative regulation by thyroid hormone receptor β1 (TRβ1) identified by genome-wide profiling of binding sites in mouse liver.
abstract: Triiodothyronine (T3) regulates key metabolic processes in the liver through the thyroid hormone receptor, TRβ1. However, the number of known target genes directly regulated by TRβ1 is limited, and the mechanisms by which positive and especially negative transcriptional regulation occur are not well understood. To characterize the TRβ1 cistrome in vivo, we expressed a biotinylated TRβ1 in hypo- and hyperthyroid mouse livers, used ChIP-seq to identify genomic TRβ1 targets, and correlated these data with gene expression changes. As with other nuclear receptors, the majority of TRβ1 binding sites were not in proximal promoters but in the gene body of known genes. Remarkably, T3 can dictate changes in TRβ1 binding, with strong correlation to T3-induced gene expression changes, suggesting that differential TRβ1 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 TRβ1 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 TRβ1 in vivo.
authors.affiliation: From the Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02115.
authors.forename: Preeti
authors.initials: P
authors.lastname: Ramadoss
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Abraham
authors.forename: Linus
authors.initials: L
authors.lastname: Tsai
authors.forename: Yiming
authors.initials: Y
authors.lastname: Zhou
authors.forename: Ricardo H
authors.initials: RH
authors.lastname: Costa-e-Sousa
authors.forename: Felix
authors.initials: F
authors.lastname: Ye
authors.forename: Martin
authors.initials: M
authors.lastname: Bilban
authors.forename: Keji
authors.initials: K
authors.lastname: Zhao
authors.forename: Anthony N
authors.initials: AN
authors.lastname: Hollenberg
mesh_terms: D000818:Animals; D002460:Cell Line; D005786:Gene Expression Regulation / Q000502:physiology*; D055106:Genome-Wide Association Study; D006801:Humans; D008099:Liver / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D020218:Response Elements / Q000502:physiology*; D037042:Thyroid Hormone Receptors beta / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000502:physiology*; D014284:Triiodothyronine / Q000378:metabolism*
chemical_list: D037042:Thyroid Hormone Receptors beta; D014284:Triiodothyronine
keywords: ChIP-seq; Chromatin Immunoprecipitation (ChIP); Nuclear Receptors; TRb1; Thyroid Hormone; Thyroid Hormone Receptor; Transcription Regulation; Transcription Target Genes; gpd2; thrsp