title: Thyroid hormone signaling in vivo requires a balance between coactivators and corepressors.
abstract: Resistance to thyroid hormone (RTH), a human syndrome, is characterized by high thyroid hormone (TH) and thyroid-stimulating hormone (TSH) levels. Mice with mutations in the thyroid hormone receptor beta (TRβ) gene that cannot bind steroid receptor coactivator 1 (SRC-1) and Src-1(-/-) mice both have phenotypes similar to that of RTH. Conversely, mice expressing a mutant nuclear corepressor 1 (Ncor1) allele that cannot interact with TRβ, termed NCoRΔID, have low TH levels and normal TSH. We hypothesized that Src-1(-/-) mice have RTH due to unopposed corepressor action. To test this, we crossed NCoRΔID and Src-1(-/-) mice to create mice deficient for coregulator action in all cell types. Remarkably, NCoR(ΔID/ΔID) Src-1(-/-) mice have normal TH and TSH levels and are triiodothryonine (T(3)) sensitive at the level of the pituitary. Although absence of SRC-1 prevented T(3) activation of key hepatic gene targets, NCoR(ΔID/ΔID) Src-1(-/-) mice reacquired hepatic T(3) sensitivity. Using in vivo chromatin immunoprecipitation assays (ChIP) for the related coactivator SRC-2, we found enhanced SRC-2 recruitment to TR-binding regions of genes in NCoR(ΔID/ΔID) Src-1(-/-) mice, suggesting that SRC-2 is responsible for T(3) sensitivity in the absence of NCoR1 and SRC-1. Thus, T(3) targets require a critical balance between NCoR1 and SRC-1. Furthermore, replacement of NCoR1 with NCoRΔID corrects RTH in Src-1(-/-) mice through increased SRC-2 recruitment to T(3) target genes.
authors.affiliation: Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Kristen R
authors.initials: KR
authors.lastname: Vella
authors.forename: Preeti
authors.initials: P
authors.lastname: Ramadoss
authors.forename: Ricardo H
authors.initials: RH
authors.lastname: Costa-E-Sousa
authors.forename: Inna
authors.initials: I
authors.lastname: Astapova
authors.forename: Felix D
authors.initials: FD
authors.lastname: Ye
authors.forename: Kaila A
authors.initials: KA
authors.lastname: Holtz
authors.forename: Jamie C
authors.initials: JC
authors.lastname: Harris
authors.forename: Anthony N
authors.initials: AN
authors.lastname: Hollenberg
mesh_terms: D000818:Animals; D056970:Co-Repressor Proteins / Q000378:metabolism*; D005260:Female; D017353:Gene Deletion; D006801:Humans; D008297:Male; D051379:Mice; D009154:Mutation; D056920:Nuclear Receptor Coactivator 1 / Q000235:genetics / Q000378:metabolism*; D051958:Nuclear Receptor Coactivator 2 / Q000378:metabolism*; D010902:Pituitary Gland / Q000378:metabolism; D015398:Signal Transduction; D037042:Thyroid Hormone Receptors beta / Q000235:genetics / Q000378:metabolism; D018382:Thyroid Hormone Resistance Syndrome / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D013963:Thyroid Hormones / Q000097:blood / Q000378:metabolism*; D013972:Thyrotropin / Q000097:blood / Q000378:metabolism; D014284:Triiodothyronine / Q000378:metabolism
chemical_list: D056970:Co-Repressor Proteins; D051958:Nuclear Receptor Coactivator 2; D037042:Thyroid Hormone Receptors beta; D013963:Thyroid Hormones; D014284:Triiodothyronine; D013972:Thyrotropin; D056920:Nuclear Receptor Coactivator 1