Anemerginghallmarkofcancerisepigeneticalteration,whichoftenresultsdirectlyfromsomaticmutationsof genes encoding chromatin factors or secondarily from hyperactive signal transduction or metabolic changes. Theseepigeneticchangesinturnrendercancercellshighlyreliantonthechromatinmachinerytomaintainthe malignant state, thus creating opportunities for therapeutic intervention by targeting chromatin. Histone post- translationalmodifications(PTMs)carryanepigeneticlayerofmessagethatcanberecognizedanddecodedby dedicated protein ?readers? to regulate fundamental DNA-templated processes. Therefore, these recognition eventsconstitutekeymechanismsunderlyingtranscriptionalcontrolincancer.WerecentlydiscoveredthatENL, aYEATSdomain-containingprotein,actsasanovelreaderforhistoneacetylationtoregulateoncogenicgene expression and is essential for the maintenance of a wide range of aggressive leukemia. Structural study revealed an acetyl-lysine binding pocket in the ENL YEATS domain that is amenable for drug targeting. Furthermore,recurrentmutationsintheENLYEATSdomainwererecentlyreportedinWilmstumor,themost common kidney tumor in children and associated with poor outcome, indicating a broad and important role of ENL in cancer. The goal of this project is to fully elucidate the mechanisms by which ENL and its tumor- associatedmutationsestablishand/ormaintainthemalignantstateincancer.Duringthementoredphaseofthe award,thePIwillapplyinnovativeapproachestoidentifythecombinatoryhistonecodesandDNA-bindingfactors that determine the gene-specific targeting of ENL (Aim 1). The PI will also identify and characterize effector proteinsthatmediatethegeneregulatoryfunctionofENLinleukemia(Aim2).Duringtheindependentphase, thePIproposestostudytherolesoftumor-associatedENLYEATSmutationsbytestingthehypothesisthatthe mutationsconfergainoffunctioninchromatintargetingandtranscriptionalcontroltodrivethedevelopmentof Wilms tumors (Aim 3). Together, results from these studies will provide novel insights into epigenetic reader- mediatedprocessesincancerandadvancetheexplorationofnewtherapeuticavenuesfortheassociatedcancer. Under the guidance of an exceptional team of mentors, the PI will acquire new training in chromatin chemical biology,computationalepigenomics,andtranscriptionregulation,whichwillcriticallycontributetothePI?scareer development and put her in a unique position to apply integrated approaches to reveal new insights into the epigeneticcontrolincancer.TheRockefellerUniversityanditsneighboringinstitutionsprovideanoutstanding environmentforthePItocarryouttheproposedstudyandtoenhanceherprofessionaldevelopment.Theaward willserveasanidealsteppingstoneforthePItotransitionintoanindependencefacultypositionandtoobtain long-termsuccessinthefieldofcancerepigenetics.
Investigating the chromatin decoding process by epigenetic reader proteins is essential not only to our basic understandingofepigeneticregulation,butalsototheclinicalexplorationofepigeneticreadersasanewclass oftherapeutictargetsincancer.Findingsfromtheproposedstudyhavegreatpotentialtopavethewaytonew treatment options for cancer such as aggressive leukemia and high-risk pediatric kidney cancer. The insights andtheframeworkgeneratedinthisstudywillgreatlybenefitfutureinvestigationofotherepigeneticregulators inadditionalcancercontexts.
