The current research is to study how epigenomic modifier histone deacetylase 3 (HDAC3) regulates carbohydratesmetabolismandinsulinsensitivityinskeletalmuscleinresponsetoeithertheinternalcircadian clockortheexternaldietaryfactor.IhavedevelopedanovelmousemodelwithHDAC3specificallydepletedin skeletal muscle, and have found that the mice display disrupted metabolic circadian gene expression and exacerbatedglucoseintolerancethatisinducedbyhighfatdiet(HFD).Duringthementoredphase,Iwillgain newexpertiseingenomewideepigenomicapproachesthatarewellestablishedinmymentor?slaboratory.I willalsogainadditionalknowledgeinmusclephysiology,metabolicfluxanalysis,andmetabolomicsmethods throughcollaborationwithotherlaboratoriesandcorefacilitiesatUniversityofPennsylvania. TheresearchthatIproposetocontinueintheindependentphaseistostudyHDAC3inexerciseendurance, fuelselectionandefficiency,aswellaslipidandaminoacidmetabolisminskeletalmuscle.Wehavefoundthat micewithoutmuscularHDAC3havesurprisinglyimprovedexerciseenduranceassociatedwithaswitchinfuel preference from carbohydrates towards lipid. I will characterize mitochondrial function and trace metabolic fluxes through lipid, ketone bodies, and amino acids catabolism, including the anaplerotic purine nucleotide cycle, in exercising animals as well as in isolated primary myocytes, where knockdown experiments will test therequirementofspecificHDAC3targetgenesfortheobservedfuelselectionandenhancedfuelefficiency. My future career goal after independence is to decipher the epigenomic mechanism that underlies hormetic responsetophysicalexerciseinskeletalmuscle.Exerciseisbeneficialtomanyaspectsofhealth,especiallyin thecontextofobesityanddiabetes.Mygeneralhypothesisisthatepigenomicmechanismsunderlieexercise induced beneficial metabolic remodeling. I will comprehensively characterize exerciseinduced changes in skeletal muscle transcriptome and epigenome using genomewide methods and metabolomics approaches. This is the first endeavor ever, as far as I know, to analyze exerciseinduced epigenomic changes in a genomewidescale.Thisunbiasedmethodwillproducecomprehensivedatasets,fromwhichdataminingand motif analysis will generate new hypotheses regarding novel transcription networks that respond to exercise. Biochemistrymethodsandmetabolicfluxanalysiswillthenbeusedtovalidatethesehypotheses,followedby development of genetic animal models and physiology studies. Together, these approaches will generate testable hypothesis backed up by preliminary data, which is essential for successful competition for future fundingopportunities.
The proposed project will examine how the internal circadian clock and the external dietary environment or physical exercise interacts with one another in regulation of skeletal muscle energy metabolism and insulin sensitivity through histone deacetylase 3 (HDAC3). Accomplishment of the project will further our understanding of how intermediary metabolism in skeletal muscle is regulated by epigenomic mechanisms, which has clinical implications given the availability of many small molecule HDAC inhibitors being tested in clinicaltrialsfortreatmentofcancerandinflammatorydiseases.
