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 newexpertiseingenomewideepigenomicapproachesthatarewellestablishedinmymentorslaboratory.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.

Public Health Relevance

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.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Transition Award (R00)
Project #
Application #
Study Section
Special Emphasis Panel (NSS)
Program Officer
Silva, Corinne M
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Baylor College of Medicine
Internal Medicine/Medicine
Schools of Medicine
United States
Zip Code
Koerner, Martha V; FitzPatrick, Laura; Selfridge, Jim et al. (2018) Toxicity of overexpressed MeCP2 is independent of HDAC3 activity. Genes Dev 32:1514-1524
Gong, Yingyun; Cao, Rui; Ding, Guolian et al. (2018) Integrated omics approaches to characterize a nuclear receptor corepressor-associated histone deacetylase in mouse skeletal muscle. Mol Cell Endocrinol 471:22-32
Poleshko, Andrey; Shah, Parisha P; Gupta, Mudit et al. (2017) Genome-Nuclear Lamina Interactions Regulate Cardiac Stem Cell Lineage Restriction. Cell 171:573-587.e14
Hong, Sungguan; Zhou, Wenjun; Fang, Bin et al. (2017) Dissociation of muscle insulin sensitivity from exercise endurance in mice by HDAC3 depletion. Nat Med 23:223-234
Papazyan, Romeo; Sun, Zheng; Kim, Yong Hoon et al. (2016) Physiological Suppression of Lipotoxic Liver Damage by Complementary Actions of HDAC3 and SCAP/SREBP. Cell Metab 24:863-874
Zhang, Liguo; He, Xuelian; Liu, Lei et al. (2016) Hdac3 Interaction with p300 Histone Acetyltransferase Regulates the Oligodendrocyte and Astrocyte Lineage Fate Switch. Dev Cell 36:316-30
Zhu, Liangru; Zou, Fang; Yang, Yongjie et al. (2015) Estrogens prevent metabolic dysfunctions induced by circadian disruptions in female mice. Endocrinology 156:2114-23
Loro, Emanuele; Seifert, Erin L; Moffat, Cynthia et al. (2015) IL-15R? is a determinant of muscle fuel utilization, and its loss protects against obesity. Am J Physiol Regul Integr Comp Physiol 309:R835-44
Zhang, Yuxiang; Fang, Bin; Emmett, Matthew J et al. (2015) GENE REGULATION. Discrete functions of nuclear receptor Rev-erb? couple metabolism to the clock. Science 348:1488-92
Fang, Bin; Everett, Logan J; Jager, Jennifer et al. (2014) Circadian enhancers coordinate multiple phases of rhythmic gene transcription in vivo. Cell 159:1140-1152