MolecularCellReviewProtein-BasedInheritance:EpigeneticsbeyondtheChromosomeZacharyH.Harvey,1,3YiwenChen,1,3andDanielF.Jarosz1,2,*1DepartmentofChemicalandSystemsBiology2DepartmentofDevelopmentalBiologyStanfordUniversitySchoolofMedicine,269CampusDrive,Stanford,CA94305,USA3Theseauthorscontributedequally*Correspondence:jarosz@stanford.eduhttps://doi.org/10.1016/j.molcel.2017.10.030EpigeneticsreferstochangesinphenotypethatarenotrootedinDNAsequence.Thisphenomenonhaslargelybeenstudiedinthecontextofchromatinmodification.Yetmanyepigenetictraitsareinsteadlinkedtoself-perpetuatingchangesintheindividualorcollectiveactivityofproteins.Mostsuchproteinsareprions(e.g.,[PSI+],[URE3],[SWI+],[MOT3+],[MPH1+],[LSB+],and[GAR+]),whichhavethecapacitytoadoptatleastoneconformationthatself-templatesoverlongbiologicaltimescales.Thisallowsthemtoserveasprotein-basedepigeneticelementsthatarereadilybroadcastthroughmitosisandmeiosis.Insomecircumstances,self-templatingcanfueldisease,butitalsopermitsaccesstomultipleactivitystatesfromthesamepolypep-tideandtransmissionofthatinformationacrossgenerations.Ensuingphenotypicchangesallowgeneticallyidenticalcellstoexpressdiverseandfrequentlyadaptivephenotypes.Althoughlongthoughttoberare,pro-tein-basedepigeneticinheritancehasnowbeenuncoveredinalldomainsoflife.OurmodernviewofepigeneticstracesitsoriginstoWaddington,whoderivedthetermfromAristotle’sideaofepigenesistodescribethedivergencebetweengenotypeandphenotypedur-ingdevelopment(Waddington,1942).Sincethen,themeaningofepigeneticshasbeenrefinedtoreflectgrowingmolecularin-sights.ItnowmorecommonlyreferstoheritablealterationsingeneexpressionthatdonotarisefromalteredDNAsequence,usuallychangesinchromatinsuchasDNAmethylation,histonemodification,andnucleosomepositioning(HollidayandPugh,1975;Nanney,1958;Riggs,1975).Onefascinatingbutoftenoverlookedmodeofepigeneticinheritanceisnotlinkedtochangesinchromosomes.Rather,newbiologicaltraitscanemergefromheritablechangesintheindividualorcollectiveac-tivityofproteinsknownasprions...
