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

Significance Thyroid hormone receptors (TRs) mediate the genomic actions of thyroid hormones. In the absence of T3 (3,3′,5-triiodothyronine), the TR recruits a multiprotein repressor complex that decreases histone acetylation in the vicinity of target genes. Nuclear receptor corepressor 1 (NCoR1) is hypothesized to be the main corepressor that interacts with TR. Here we report that the deletion of NCoR1 does not prevent all gene repression and histone deacetylation across a variety of mouse models, whereas only the lack of TR was able to overturn the effects of hypothyroidism. Thus, we conclude that NCoR1 is not sufficient to mediate the actions of the unliganded TR; furthermore, our data suggest that alternative mechanisms of repression may be involved in the action of TRs. 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.