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

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