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.
journal_name
Hum Mol Genetjournal_title
Human molecular geneticsauthors
Kim DW,Park JW,Willingham MC,Cheng SYdoi
10.1093/hmg/ddt660subject
Has Abstractpub_date
2014-05-15 00:00:00pages
2651-64issue
10eissn
0964-6906issn
1460-2083pii
ddt660journal_volume
23pub_type
杂志文章abstract::Deletions within the neurexin 1 gene (NRXN1; 2p16.3) are associated with autism and have also been reported in two families with schizophrenia. We examined NRXN1, and the closely related NRXN2 and NRXN3 genes, for copy number variants (CNVs) in 2977 schizophrenia patients and 33 746 controls from seven European popula...
journal_title:Human molecular genetics
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journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddp551
更新日期:2010-03-01 00:00:00
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journal_title:Human molecular genetics
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doi:10.1093/hmg/9.8.1245
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journal_title:Human molecular genetics
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journal_title:Human molecular genetics
pub_type: 杂志文章,评审
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更新日期:2017-08-01 00:00:00
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更新日期:1996-02-01 00:00:00
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journal_title:Human molecular genetics
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更新日期:2016-09-15 00:00:00
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journal_title:Human molecular genetics
pub_type: 杂志文章,评审
doi:10.1093/hmg/ddh074
更新日期:2004-04-01 00:00:00
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journal_title:Human molecular genetics
pub_type: 杂志文章
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更新日期:2016-03-01 00:00:00
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journal_title:Human molecular genetics
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journal_title:Human molecular genetics
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journal_title:Human molecular genetics
pub_type: 杂志文章
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更新日期:2012-03-15 00:00:00
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journal_title:Human molecular genetics
pub_type: 杂志文章
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更新日期:2015-03-01 00:00:00
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journal_title:Human molecular genetics
pub_type: 杂志文章,评审
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journal_title:Human molecular genetics
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更新日期:2012-02-15 00:00:00
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