title: A histone deacetylase inhibitor improves hypothyroidism caused by a TRα1 mutant.
abstract: Mutations of the thyroid hormone receptor α gene (THRA) cause hypothyroidism in patients with growth and developmental retardation, and skeletal dysplasia. Genetic evidence indicates that the dominant negative activity of TRα1 mutants underlies pathological manifestations. Using a mouse model of hypothyroidism caused by a dominant negative TRα1PV mutant and its derived mouse model harboring a mutated nuclear receptor corepressor (NCOR1ΔID) (Thra1(PV/+)Ncor1(ΔID/ΔID) mice), we recently showed that aberrant release of TRα1 mutants from the NCOR1 repressor complex mediates dominant negative actions of TRα1 mutants in vivo. We tested the hypothesis that deacetylation of nucleosomal histones associated with aberrant recruitment of corepressors by TRα1 mutants underlies pathological phenotypic expression. We treated Thra1(PV/+)and Thra1(PV/+)Ncor1(ΔID/ΔID) 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(ΔID/ΔID) 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/ebpα and Pparγ, 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 TRα1 mutants. Importantly, for the first time, the present studies show that HDAC inhibitors are clearly beneficial for hypothyroidism and could be therapeutics for treatment.
authors.affiliation: Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Dong Wook
authors.initials: DW
authors.lastname: Kim
authors.forename: Jeong Won
authors.initials: JW
authors.lastname: Park
authors.forename: Mark C
authors.initials: MC
authors.lastname: Willingham
authors.forename: Sheue-yann
authors.initials: SY
authors.lastname: Cheng
mesh_terms: D050156:Adipogenesis / Q000187:drug effects / Q000235:genetics; D000818:Animals; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D044127:Epigenesis, Genetic / Q000187:drug effects; D015870:Gene Expression; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D006655:Histone Deacetylases / Q000378:metabolism; D006877:Hydroxamic Acids / Q000494:pharmacology / Q000627:therapeutic use*; D007037:Hypothyroidism / Q000097:blood / Q000188:drug therapy* / Q000235:genetics; D050152:Intra-Abdominal Fat / Q000187:drug effects / Q000473:pathology; D008297:Male; D008822:Mice, Transgenic; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D037021:Thyroid Hormone Receptors alpha / Q000235:genetics*; D013963:Thyroid Hormones / Q000097:blood; D000077337:Vorinostat; D015430:Weight Gain / Q000187:drug effects; D000099186:Histone Deacetylase 3
chemical_list: D022762:CCAAT-Enhancer-Binding Proteins; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases; D006877:Hydroxamic Acids; D047495:PPAR gamma; D037021:Thyroid Hormone Receptors alpha; D013963:Thyroid Hormones; D000077337:Vorinostat; D000099186:Histone Deacetylase 3; C530718:CEBPA protein, mouse