Thyroid hormone signaling in vivo requires a balance between coactivators and corepressors.

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Vella, KR; Ramadoss, P; Costa-E-Sousa, RH; Astapova, I; Ye, FD; Holtz, KA; Harris, JC; Hollenberg, AN

Published Date

  • May 2014

Published In

Volume / Issue

  • 34 / 9

Start / End Page

  • 1564 - 1575

PubMed ID

  • 24550004

Pubmed Central ID

  • 24550004

Electronic International Standard Serial Number (EISSN)

  • 1098-5549

Digital Object Identifier (DOI)

  • 10.1128/MCB.00129-14

Language

  • eng

Conference Location

  • United States