Letterhttps://doi.org/10.1038/s41586-018-0239-3EpigeneticinheritancemediatedbycouplingofRNAiandhistoneH3K9methylationrubyYu1,XiaoyiWang1&DaneshMoazed1*Histonepost-translationalmodifications(PTMs)areassociatedwithepigeneticstatesthatformthebasisforcell-type-specificgeneexpression1,2.Onceestablished,histonePTMscanbemaintainedbypositivefeedbackinvolvingenzymesthatrecognizeapre-existinghistonemodificationandcatalysethesamemodificationonnewlydepositedhistones.Recentstudiessuggestthatinwild-typecells,histonePTM-basedpositivefeedbackistooweaktomediateepigeneticinheritanceintheabsenceofotherinputs3–7.RNAinterference(RNAi)-mediatedhistoneH3lysine9methylation(H3K9me)andheterochromatinformationdefineapotentialepigeneticinheritancemechanisminwhichpositivefeedbackinvolvingshortinterferingRNA(siRNA)amplificationcanbedirectlycoupledtohistonePTMpositivefeedback8–14.However,itisnotknownwhetherthecouplingofthesetwofeedbackloopscanmaintainepigeneticsilencingindependentlyofDNAsequenceandintheabsenceofenablingmutationsthatdisruptgenome-widechromatinstructureortranscription15–17.Here,usingthefissionyeastSchizosaccharomycespombe,weshowthatsiRNA-inducedH3K9meandsilencingofaeuchromaticgenecanbeepigeneticallyinheritedincisduringmultiplemitoticandmeioticcelldivisionsinwild-typecells.ThisinheritanceinvolvesthespreadingofsecondarysiRNAsandH3K9me3tothetargetedgeneandsurroundingareas,andrequiresbothRNAiandH3K9me,suggestingthatthesiRNAandH3K9mepositive-feedbackloopsactsynergisticallytomaintainsilencing.Bycontrast,whenmaintainedsolelybyhistonePTMpositivefeedback,silencingiserasedbyH3K9demethylationpromotedbyEpe1,orbyinterallelicinteractionsthatoccuraftermatingtocellscontaininganexpressedalleleevenintheabsenceofEpe1.ThesefindingsdemonstratethattheRNAimachinerycanmediatetransgenerationalepigeneticinheritanceindependentlyofDNAsequenceorenablingmutations,andrevealaroleforthecouplingofthesiRNAandH3K9mepositive-feedbackloopsintheprotectionofepigeneticallelesfromerasure.TodeterminewhethersiRNApositi...
