| First Author | Kim DW | Year | 2014 |
| Journal | Hum Mol Genet | Volume | 23 |
| Issue | 10 | Pages | 2651-64 |
| PubMed ID | 24381310 | Mgi Jnum | J:209162 |
| Mgi Id | MGI:5566571 | Doi | 10.1093/hmg/ddt660 |
| Citation | Kim DW, et al. (2014) A histone deacetylase inhibitor improves hypothyroidism caused by a TRalpha1 mutant. Hum Mol Genet 23(10):2651-64 |
| abstractText | Mutations of the thyroid hormone receptor alpha gene (THRA) cause hypothyroidism in patients with growth and developmental retardation, and skeletal dysplasia. Genetic evidence indicates that the dominant negative activity of TRalpha1 mutants underlies pathological manifestations. 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) (Thra1(PV/+)Ncor1(DeltaID/DeltaID) 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 Thra1(PV/+)and Thra1(PV/+)Ncor1(DeltaID/DeltaID) mice with a histone deacetylase (HDAC) inhibitor, suberoylanilide hydroxyamic acid (SAHA). SAHA significantly ameliorated the impaired growth, bone development and adipogenesis of Thra1(PV/+) mice. In Thra1(PV/+)Ncor1(DeltaID/DeltaID) 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, C/ebpalpha and Ppargamma, 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 confers 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. |
