TheimpactofcellularmetabolismonchromatindynamicsandepigeneticsMichaelA.Reid1,ZiweiDai1,andJasonW.Locasale1,*1DepartmentofPharmacologyandCancerBiology,DukeCancerInstitute,DukeMolecularPhysiologyInstitute,DukeUniversitySchoolofMedicine,Durham,NorthCarolina,27710,USAAbstractThesubstratesusedtomodifynucleicacidsandchromatinareaffectedbynutrientavailabilityandtheactivityofmetabolicpathways.Thus,cellularmetabolismconstitutesafundamentalcomponentofchromatinstatusandtherebyofgenomeregulation.Herewedescribethebiochemicalandgeneticprinciplesofhowmetabolismcaninfluencechromatinbiologyandepigenetics,discussthefunctionalrolesofthisinterplayindevelopmentalandcancerbiology,andpresentfuturedirectionsinthisrapidlyemergingarea.IntroductionOrganismalmetabolismbeginswiththeingestionofnutrientsfromfoodsources.Itcontinueswiththeprocessingofthesenutrientsinthegut,whichtheninteractswiththemicrobiome,liver,pancreas,muscle,andmanyotherorganstoresultinasetofcompoundsthatcirculateintheplasma1.Cellstakeuptheseplasma-suppliednutrientsalongwithothercomponentsprovidedbytheirmicroenvironment2,3,andusethemtocreatecellularmetabolicnetworksthatareorganizedthroughinterconnectedchemicalreactionswiththousandsofmetaboliteslinkedbycommensuratenumbersofreactions.Metabolicnetworkactivityischaracterizedbytheconcentrationsofintermediatemetabolitesandtherates(i.e.fluxes)atwhichonemetaboliteisconvertedtoanother,andismediatedbygenotype,epigenotype,andenvironmentalinputssuchasnutrientavailability,andtheengagementofsignalingpathways3–6.ChromatinistheintracellularstructurethatpackagesDNAineukaryoticcells.Theprincipalunitofchromatinorganizationisthenucleosome,whichisformedbyDNAwrappedaroundanoctamerofhistoneproteins.Chromatincanexistindifferentstablestatesandisalteredbycovalentmodificationsonthehistonesalongwiththepresenceofmanyotherfactorssuchaslongnon-codingRNAs,proteinchaperones,andchromatinremodelingenzymes7–10.Thesemodificationsinfluencechromatinstructureandbindingofchromatinremodelingenzymesandtranscriptio...
