《Multifaceted roles of miR-ls in repressing the fetal gene program in the heart.》.pdf

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《Multifaceted roles of miR-ls in repressing the fetal gene program in the heart.》.pdf

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CellResearch(2014)24：278-292． @2014IBCB，SIBS，CAS Allrightsresewed1001—0602／14$32．00 ORIGINALARTICLE 1^n^n^f．nature．com／cr Multifacetedrolesofm - 7Sinrepressingthefetalgene program inthehea 一一 YushengWei’’，SiwuPeng’，MengWu ，RaviSachidanandam ，ZhidongTu，ShihongZhang， ChristineFalce，EricASobie，DjamelLebeche，YongZhao MindichChiMHealthandDevelopmentInstitute，DepartmentofGeneticsandGenomicSciences，IcahnSchoolofMedicineat MountSinai,OneGustaveL．LevyPlace,Box1040,NewYork,NY10029,USA,2InstituteforGenomicsandMultiscaleBiology, lcahnSchoolofMedicineatMountSinai,OneGustaveL．LevyPlace，NewYork,NY10029，USA,CardiovascularInstitute， IcahnSchoolofMedicineatMountSinai,OneGustaveL．LevyPlace,NewYork,NY10029,USA；4pharmacoloyg andSystems TherapeuticsIcahnSchoolofMedicineatMountSinai,OneGustaveL．LewPlace,NewYork．NY10029,USA miRNAsareanimportantclassofregulatorsthatplayrolesincellularhomeostasisanddisease．Muscle-specific m ilNAs。m ／R．1．1andm ／R．1．2，havebeenfoundtoplayimportantrolesinregulatingcellproliferationandcardiac funetion．Redundancybetweenm ／R．1．1andm ／R．1．2haspreviously impededafullunderstandingoftheirroles／n vivo．T0determ inehow miR．Isregulatecardiacfunotion invivo．wegenerated micelackingm／R一1—1andmiR一1—2 withoutaffectingnearbygenes．mR／．1doubleknockout(mR／一1dKo1micewereviableandnotsignificantlydifferent fromwild．typecontrolsatpostnatalday2．5．Thereafter,allmR／一1dKOmicedevelopeddilatedcardiomyopathy(DCM) anddiedbeforeP17．M assivelyparallelsequencingshowedthatalargeportionofupregulatedgenesafterdeletionof m ／R—Isisassociatedwiththecardiacfetalgeneprogram includingcellproliferation，glycolysis，glycogenesis，andfetal sarcomere-associatedgenes．Consistentwithgeneprofiling，glycogencontentandglycolyticratesweresignificantly increasedinmR／1dKOmice．Es~ogen．relatedReceptor (E