MetabolicregulationofgeneexpressionthroughhistoneacylationsBenjaminR.Sabari1,*,DiZhang2,*,C.DavidAllis1,§,andYingmingZhao2,§1LaboratoryofChromatinBiologyandEpigenetics,TheRockefellerUniversity,NewYork,NY10065,USA2BenMayDepartmentofCancerResearch,TheUniversityofChicago,Chicago,IL60637,USAAbstractEighttypesofshort-chainlysine(Lys)acylationshaverecentlybeenidentifiedonhistones:propionylation,butyrylation,2-hydroxyisobutyrylation,succinylation,malonylation,glutarylation,crotonylationandβ-hydroxybutyrylation.EmergingevidencesuggestthatthesehistonemodificationsaffectgeneexpressionandarestructurallyandfunctionallydifferentfromthewidelystudiedhistoneLysacetylation.Inthisreview,wediscusstheregulationofnon-acetylhistoneacylationbyenzymaticandmetabolicmechanisms,acylation“reader”proteinsthatmediatetheeffectsofdifferentacylations,andtheirphysiologicalfunctions,includinginsignal-dependentgeneactivation,spermatogenesis,tissueinjuryandmetabolic-inducedstress.Weproposeamodeltoexplainourpresentunderstandingofhowdifferentialhistoneacylationisregulatedbymetabolismofthedifferentacyl-CoAforms,whichinturnmodulatetheregulationofgeneexpression.IntroductionHistoneproteinsaresubjecttoawidevarietyofpost-translationalmodifications(PTMs),which,aloneorincombination,characterizeandshapefunctionalchromatinstates.MisregulationofhistonePTMpatterninghasbeenintimatelylinkedtoanumberofdiseases,includingdevelopmentalandneurologicaldisordersaswellasvariousetiologiesofcancer1-5.Withtheapplicationofhigh-sensitivitymassspectrometrytotheidentificationofhistonePTMs,thecurrentcatalogueofobservedhistonemodificationsisimmenseandgrowing6.ThemajorityofnovelhistonePTMsisclassifiedasshort-chainLysacylations.Thesemodificationsaresimilartothewell-studiedLysacetylation(Kac)intheirε-aminelinkage,yetdistinctintheirhydrocarbonchainlength,hydrophobicityorcharge.Sofarthenewlydiscoveredshort-chainLysacylationsincludehistoneLyspropionylation(Kpr)7,butyrylation(Kbu)7,2-hydroxyisobutyrylation(Khib)8,succinylation(Ksucc...
