NCoR1-independent mechanism plays a role in the action of the unliganded thyroid hormone receptor.

Journal Article (Journal Article)

Nuclear receptor corepressor 1 (NCoR1) is considered to be the major corepressor that mediates ligand-independent actions of the thyroid hormone receptor (TR) during development and in hypothyroidism. We tested this by expressing a hypomorphic NCoR1 allele (NCoR1ΔID), which cannot interact with the TR, in Pax8-KO mice, which make no thyroid hormone. Surprisingly, abrogation of NCoR1 function did not reverse the ligand-independent action of the TR on many gene targets and did not fully rescue the high mortality rate due to congenital hypothyroidism in these mice. To further examine NCoR1's role in repression by the unliganded TR, we deleted NCoR1 in the livers of euthyroid and hypothyroid mice and examined the effects on gene expression and enhancer activity measured by histone 3 lysine 27 (H3K27) acetylation. Even in the absence of NCoR1 function, we observed strong repression of more than 43% of positive T3 (3,3',5-triiodothyronine) targets in hypothyroid mice. Regulation of approximately half of those genes correlated with decreased H3K27 acetylation, and nearly 80% of these regions with affected H3K27 acetylation contained a bona fide TRβ1-binding site. Moreover, using liver-specific TRβ1-KO mice, we demonstrate that hypothyroidism-associated changes in gene expression and histone acetylation require TRβ1. Thus, many of the genomic changes mediated by the TR in hypothyroidism are independent of NCoR1, suggesting a role for additional signaling modulators in hypothyroidism.

Full Text

Duke Authors

Cited Authors

  • Mendoza, A; Astapova, I; Shimizu, H; Gallop, MR; Al-Sowaimel, L; MacGowan, SMD; Bergmann, T; Berg, AH; Tenen, DE; Jacobs, C; Lyubetskaya, A; Tsai, L; Hollenberg, AN

Published Date

  • October 3, 2017

Published In

Volume / Issue

  • 114 / 40

Start / End Page

  • E8458 - E8467

PubMed ID

  • 28923959

Pubmed Central ID

  • PMC5635887

Electronic International Standard Serial Number (EISSN)

  • 1091-6490

Digital Object Identifier (DOI)

  • 10.1073/pnas.1706917114

Language

  • eng

Conference Location

  • United States