1). A histone deacetylase inhibitor improves hypothyroidism caused by a TRalpha1 mutant Using a mouse model of hypothyroidism caused by a dominant negative TRalpha1PV mutant and its derived mouse model harboring a mutated nuclear receptor corepressor (NCOR1deltaID) (TRalpha1PV/+Ncor1deltaID mice), we recently showed that aberrant release of TRalpha1 mutants from the NCOR1 repressor complex mediates dominant negative actions of TRalpha1 mutants in vivo. We tested the hypothesis that deacetylation of nucleosomal histones associated with aberrant recruitment of corepressors by TRalpha1 mutants underlies pathological phenotypic expression. We treated TRalpha1PV/+ mice and TRalpha1PV/+Ncor1deltaID mice with a histone deacetylase (HDAC) inhibitor, SAHA. SAHA significantly ameliorated the impaired growth, bone development, and adipogenesis of TRalpha1PV/+ mice. In TRalpha1PV/+Ncor1deltaID mice, SAHA improved these abnormalities even further. We focused our molecular analyses on how SAHA improved the impaired adipogenesis leading to the lean phenotype. We found that SAHA reverted the impaired adipogenesis by de-repressing the expression of the two master regulators of adipogenesis, CCAAT/enhancer-binding protein alpha gene and peroxisome-proliferator activated receptor gamma, as well as other adipogenic genes at both the mRNA and protein levels. Chromatin immunoprecipitation analyses indicated SAHA increased the extent of acetylation of nucleosomal H4K5 and H3 to re-activate adipogenic genes to reverting adipogenesis. Thus, HDAC, confer in vivo aberrant actions of TRalpha1 mutants. Importantly, for the first time, the present studies show that HDAC inhibitors are clearly beneficial for hypothyroidism and could be therapeutics for treatment. 2). Thyroid hormone receptor alpha mutation causes a severe and thyroxine-resistant skeletal dysplasia In an attempt to improve developmental delay and alleviate symptoms of hypothyroidism caused by mutations of the THRA gene, patients are receiving varying doses and durations of L-thyroxine (T4) treatment but responses have been inconsistent so far. TRalpha1PV/+ mice express a similar potent dominant-negative mutant TRalpha1 to affected individuals, and thus represent an excellent disease model. We hypothesized that TRalpha1PV/+ mice could be used to predict the skeletal outcome of human THRA mutations and determine whether prolonged treatment with a supra-physiological dose of T4 ameliorates the skeletal abnormalities. Adult female TRalpha1PV/+ mice had short stature, grossly abnormal bone morphology but normal bone strength despite high bone mass. Although T4 treatment suppressed TSH secretion, it had no effect on skeletal maturation, linear growth or bone mineralization, thus demonstrating profound tissue resistance to thyroid hormone. Despite this, prolonged T4 treatment abnormally increased bone stiffness and strength, suggesting the potential for detrimental consequences in the long-term. Our studies establish that TRalpha1 has an essential role in the developing and adult skeleton, and predict that patients with different THRA mutations will display variable responses to T4 treatment, which depend on the severity of the causative mutation.
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