Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 114, Issue 40, Pages E8458-E8467Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1706917114
Keywords
hypothyroidism; gene repression; TR beta 1; negative regulation; histone acetylation
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Funding
- Mexican National Council for Science and Technology [250095]
- American Diabetes Association [1-17-PMF-007]
- Hearst Foundation
- Boston Nutrition Obesity Research Center Functional Genomics [P30 DK046200]
- NIH [DK056123, DK098525]
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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 (NCoR1 Delta ID), 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 TR beta 1-binding site. Moreover, using liver-specific TR beta 1-KO mice, we demonstrate that hypothyroidism-associated changes in gene expression and histone acetylation require TR beta 1. 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.
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