ALongncRNALinksCopyNumberVariationtoaPolycomb/TrithoraxEpigeneticSwitchinFSHDMuscularDystrophyDaphneS.Cabianca,1ValentinaCasa,1,2BeatriceBodega,3,5AlexandrosXynos,1EnricoGinelli,3YujiroTanaka,4andDavideGabellini1,*1DulbeccoTelethonInstituteatSanRaffaeleScientificInstitute,DivisionofRegenerativeMedicine,StemCells,andGeneTherapy,20132Milan,Italy2Universita`Vita-SaluteSanRaffaele,20132Milan,Italy3DepartmentofBiologyandGeneticsforMedicalSciences,UniversityofMilan,20133Milan,Italy4GenomeStructureandRegulation,SchoolofBiomedicalScienceandBiochemicalGenetics,MedicalResearchInstitute,TokyoMedicalandDentalUniversity,Tokyo113-8510,Japan5Presentaddress:DulbeccoTelethonInstituteatFondazioneSantaLucia,00143Rome,Italy*Correspondence:gabellini.davide@hsr.itDOI10.1016/j.cell.2012.03.035SUMMARYunits.D4Z4isextremelypolymorphicinthegeneralpopulationandbelongstoafamilyofhumannoncentromericallylocatedRepetitivesequencesaccountformorethan50%oftandemrepeatstermedmacrosatellites(Chadwick,2009).thehumangenome.FacioscapulohumeralmuscularSeveralFSHDfeatures,suchasvariabilityinseverityandratedystrophy(FSHD)isanautosomal-dominantdiseaseofprogression,genderbiasinpenetrance,asymmetricmuscleassociatedwithreductioninthecopynumberofthewasting,andmonozygotictwindiscordance,stronglysuggestD4Z4repeatmappingto4q35.Byanunknowntheinvolvementofepigeneticfactors(NeguemborandGabellini,mechanism,D4Z4deletioncausesanepigenetic2010).Accordingly,DNAmethylation(vanOverveldetal.,2003),histonemarks(Bodegaetal.,2009;Zengetal.,2009),andhigherswitchleadingtode-repressionof4q35genes.orderchromatinstructure(Bodegaetal.,2009;Petrovetal.,HereweshowthatthePolycombgroupofepigenetic2006;Pirozhkovaetal.,2008)arealteredinFSHDpatients.TheserepressorstargetsD4Z4inhealthysubjectsandchangeshavebeenassociatedwiththeinappropriatethatD4Z4deletionisassociatedwithreducedPoly-de-repressionofseveral4q35genes,amongwhichDUX4iscombsilencinginFSHDpatients.WeidentifycurrentlytheleadingFSHDcandidate(Gabellinietal.