Epigenetic Silencing in Friedreich Ataxia Is Associated with Depletion of CTCF (CCCTC-Binding Factor) and Antisense Transcription 英文参考文献.docVIP

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Epigenetic Silencing in Friedreich Ataxia Is Associated with Depletion of CTCF (CCCTC-Binding Factor) and Antisense Transcription 英文参考文献.doc

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Epigenetic Silencing in Friedreich Ataxia Is Associated with Depletion of CTCF (CCCTC-Binding Factor) and Antisense Transcription 英文参考文献

EpigeneticSilencinginFriedreichAtaxiaIsAssociated withDepletionofCTCF(CCCTC-BindingFactor)and AntisenseTranscription IreneDeBiase1.,YogeshK.Chutake1.,PaulM.Rindler1,SanjayI.Bidichandani1,2* 1DepartmentofBiochemistryandMolecularBiology,UniversityofOklahomaHealthSciencesCenter,OklahomaCity,Oklahoma,UnitedStatesofAmerica,2Department ofPediatrics,UniversityofOklahomaHealthSciencesCenter,OklahomaCity,Oklahoma,UnitedStatesofAmerica Abstract Background: Over15inheriteddiseasesarecausedbyexpansionoftriplet-repeats.Friedreich ataxia(FRDA)patientsare homozygousforanexpandedGAAtriplet-repeatsequenceinintron1oftheFXNgene.TheexpandedGAAtriplet-repeat results in deficiency of FXN gene transcription, which is reversed via administration of histone deacetylase inhibitors indicatingthattranscriptionalsilencingisatleastpartiallyduetoanepigeneticabnormality. Methodology/Principal Findings:We foundaseveredepletion ofthechromatininsulator proteinCTCF(CCCTC-binding factor)inthe59UTRoftheFXNgeneinFRDA,andcoincidentheterochromatinformationinvolvingthe+1nucleosomevia enrichmentofH3K9me3andrecruitmentofheterochromatinprotein1.WeidentifiedFAST-1(FXNAntisenseTranscript–1), anovelantisensetranscriptthatoverlapstheCTCFbindingsiteinthe59UTR,whichwasexpressedathigherlevelsinFRDA. ThereciprocalrelationshipofdeficientFXNtranscriptandhigherlevelsofFAST-1seeninFRDAwasreproducedinnormal cellsviaknockdownofCTCF. Conclusions/Significance:CTCFdepletionconstitutesanepigeneticswitchthatresultsinincreasedantisensetranscription, heterochromatin formation and transcriptional deficiency in FRDA. These findings provide a mechanistic basis for the transcriptionalsilencingoftheFXNgeneinFRDA,andbroadenourunderstandingofdiseasepathogenesisintriplet-repeat diseases. Citation:DeBiaseI,ChutakeYK,RindlerPM,BidichandaniSI(2009)EpigeneticSilencinginFriedreichAtaxiaIsAssociatedwithDepletionofCTCF(CCCTC-Binding Factor)andAntisenseTranscription.PLoSONE4(11):e7914.doi:10.1371/journal.pone.0007914 Editor:AmandaEwartT