HDAC Inhibitors Correct Frataxin Deficiency in a Friedreich Ataxia Mouse Model 英文参考文献.docVIP

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HDAC Inhibitors Correct Frataxin Deficiency in a Friedreich Ataxia Mouse Model 英文参考文献.doc

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HDAC Inhibitors Correct Frataxin Deficiency in a Friedreich Ataxia Mouse Model 英文参考文献

HDACInhibitorsCorrectFrataxinDeficiencyina FriedreichAtaxiaMouseModel MyriamRai1,ElisabettaSoragni2,KaiJenssen2¤,RyanBurnett2,DavidHerman2,GiovanniCoppola3, DanielH.Geschwind3,JoelM.Gottesfeld2,MassimoPandolfo1* 1Laboratoire de Neurologie Expe′rimentale, Ho?pital Erasme, Universite′ Libre de Bruxelles (ULB), Brussels, Belgium, 2Department of Molecular Biology, The Scripps ResearchInstitute,LaJolla,California,UnitedStatesofAmerica,3PrograminNeurogenetics,DepartmentofNeurology,DavidGeffenSchoolofMedicine,Universityof CaliforniaLosAngeles,LosAngeles,California,UnitedStatesofAmerica Abstract Background:Friedreichataxia,anautosomalrecessiveneurodegenerativeandcardiacdisease,iscausedbyabnormallylow levelsoffrataxin,anessentialmitochondrialprotein.AllFriedreichataxiapatientscarryaGAA?TTCrepeatexpansioninthefirst intronofthefrataxingene,eitherinthehomozygousstateorincompoundheterozygositywithotherloss-of-functionmutations. The GAA expansion inhibits frataxin expression through a heterochromatin-mediated repression mechanism. Histone modifications that are characteristic of silenced genes in heterochromatic regions occur at expanded alleles in cells from Friedreichataxiapatients,includingincreasedtrimethylationofhistoneH3atlysine9andhypoacetylationofhistonesH3andH4. Methodology/Principal Findings: By chromatin immunoprecipitation, we detected the same heterochromatin marks in homozygousmicecarryinga(GAA)230repeatinthefirstintronofthemousefrataxingene(KIKImice).Theseanimalshave decreased frataxin levels and, by microarray analysis, show significant gene expression changes in several tissues. We treatedKIKImicewithanovelhistonedeacetylaseinhibitor,compound106,whichsubstantiallyincreasesfrataxinmRNA levelsincellsfromFriedreichataxiaindividuals.TreatmentincreasedhistoneH3andH4acetylationinchromatinnearthe GAArepeatandrestoredwild-typefrataxinlevelsinthenervoussystemandheart,asdeterminedbyquantitativeRT-PCR and semiquantitative western blot analysis. No toxicity was observed. F