Ahallmarkoftheimmunesystemisitsabilitytomountamoreeffectiveandrapidresponseagainstsecondary exposuretoapathogen.Themechanismsbywhichtheadaptiveimmunesystemaccomplishesthistask centeraroundDNArearrangementsandselectionofthemosteffectively-respondingcells.However,ithas recentlybecomeevidentthatinnateimmunecellsalsoexhibitmemory,andthatunlikeadaptiveimmunecells, innateimmunecellscanexhibitmemorytowardsdifferentpathogensaswellasthesameoneencountered duringtheinitialexposure.Thisprocess,calledtrainedimmunity,canpresentasenhancedprotectionfrom heterologousinfectionfollowingvaccination.Ontheotherhand,diseasescharacterizedbyinflammationmay beexacerbatedbytheinductionoftrainedimmunity.Preliminaryworkfromourlabaswellasothers?has suggestedthattrainedimmunityisdrivenbyalteredtranscriptionalresponses,withinheritedchromatin structuresplayinganimportantroleinpropagatingmemoryacrosscelldivisions.Ourstudieshavedefineda subsetofgenesthatdisplaymorerapidinductionuponasecondexposuretoastimulusinalymphocyte-to- macrophagetransdifferentiationmodel.These?memory?genesdisplayareductionintrimethylationoflysine 27ofhistoneH3(H3K27me3),andinhibitingH3K27me3demethylationresultsinimpairedmemoryformation attheseloci.Wehaveundertakenapilotunbiasedscreenforadditionalchromatinfactorsthatcouldinfluence memoryformation,andhaveidentified23genesthatscoredhighlyandarecurrentlybeingvalidated. Inthiswork,weplantoextendourfindingstomacrophagesandNKcells,twocelltypesoftheinnateimmune systemthoughttoexhibitmemory.Wewillestablishprotocolstoelicitamemoryresponseinthesecells,using stimulithatmimicpathogenexposureorcytokinesignaling,andexaminewhichgenesexhibitmemoryineach context.Usingchromatinimmunoprecipitationapproaches,wewillidentifychromatinmodificationsthat accompanytheinductionoftranscriptionalmemory,andwewillemploysmall-moleculeandshRNA-based screeningapproachestoidentifychromatinregulatorsresponsiblefortheestablishmentormaintenanceof memory.Finally,wewillextendourresultstoamousemodelofdiet-inducedobesity,apathologyexacerbated byinflammationofadiposetissuesbypro-inflammatorymacrophageactivity.Wewillexaminewhether macrophagetranscriptionalmemoryplaysaroleinasecondinductionofobesityfollowingaperiodofweight loss.Weexpectourstudiestoelucidatethechromatin-basedmolecularmechanismsunderlyingthe establishmentandmaintenanceoftranscriptionalmemory,andrevealhowthesemechanismsplayarolein thepathologicalcontextofdiet-inducedobesity.
Justlikeweashumanscanlearnfrompastexperiences,cellswithinourbodyalsohavethecapabilitytolearn afterexposuretovariousstimuliandtomaintainthismemorytoallowforcellularadaptation.Forexample,as cellsoftheimmunesystemfightoffnewinfections,theylearnfromthisexposuretoenableaquickerand betterresponseinthefuture.Intheproposedsetofexperiments,wewillexplorethedifferentmolecules involvedinestablishingcellularmemory,andhopetoexplainhowmemorycanbothhelphumansmorereadily fightdisease,andalsocontributetopathologiessuchasobesity.
