SIRT1 Inhibition Alleviates Gene Silencing in Fragile X Mental Retardation Syndrome 英文参考文献.docVIP

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SIRT1 Inhibition Alleviates Gene Silencing in Fragile X Mental Retardation Syndrome 英文参考文献.doc

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SIRT1 Inhibition Alleviates Gene Silencing in Fragile X Mental Retardation Syndrome 英文参考文献

SIRT1InhibitionAlleviatesGeneSilencinginFragileX MentalRetardationSyndrome ReaBiacsi1,2,DamanKumari1,KarenUsdin1* 1Section on Genomic Structure and Function, Laboratory of Molecular and Cellular Biology, National Institute of Diabetes, Digestive and Kidney Diseases, National InstitutesofHealth,Bethesda,Maryland,UnitedStatesofAmerica,2DoctorateSchoolofBiology,ClassicalandMolecularGeneticsBranch,DepartmentofGenetics,Eo¨tvo¨s Lo′ra′nd University,Budapest,Hungary Abstract ExpansionoftheCGGNCCG-repeattractinthe59UTRoftheFMR1geneto.200repeatsleadstoheterochromatinizationof the promoter and gene silencing. This results in Fragile X syndrome (FXS), the most common heritable form of mental retardation.Themechanismofgenesilencingisunknown.WereportherethataClassIIIhistonedeacetylase,SIRT1,playsan importantroleinthissilencingprocessandshowthattheinhibitionofthisenzymeproducessignificantgenereactivation. This contrasts with the much smaller effect of inhibitors like trichostatin A (TSA) that inhibit Class I, II and IV histone deacetylases.ReactivationofsilencedFMR1alleleswasaccompaniedbyanincreaseinhistoneH3lysine9acetylationas well as anincrease in theamount of histone H4 that is acetylated at lysine 16 (H4K16) by thehistone acetyltransferase, hMOF. DNA methylation, on the other hand, is unaffected. We also demonstrate that deacetylation of H4K16 is a key downstreamconsequenceofDNAmethylation.However,sinceDNAmethylationinhibitorsrequireDNAreplicationinorder tobeeffective,SIRT1inhibitorsmaybemoreusefulforFMR1genereactivationinpost-mitoticcellslikeneuronswherethe effectofthegenesilencingismostobvious. Citation:BiacsiR,KumariD,UsdinK(2008)SIRT1InhibitionAlleviatesGeneSilencinginFragileXMentalRetardationSyndrome.PLoSGenet4(3):e1000017. doi:10.1371/journal.pgen.1000017 Editor:HarryOrr,UniversityofMinnesota,UnitedStatesofAmerica ReceivedAugust28,2007;AcceptedFebruary5,2008;PublishedMarch14,2008 Thisisanopen-accessarticledistributedunderthetermsoftheCreativeCommonsPublicDomaindeclar