Jonathan A. Epstein, M.D.

faculty photo
William Wikoff Smith Professor of Cardiovascular Research
Department: Medicine
Graduate Group Affiliations

Contact information
Executive Vice Dean and Chief Scientific Officer
602 PCAM South Expansion
3400 Civic Center Blvd.
Philadelphia, PA 19104
Office: (215) 898-8731
Fax: (215) 573-2030
A.B. (Biochemistry)
Harvard College, 1983.
M.D. (Medicine)
Harvard Medical School, 1988.
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Description of Research Expertise

Research Interests
Transcriptional regulation of cardiac development and function using mouse models

Key words: Cardiac development, Neural crest, Transcription, Hypertrophy, Pax, Neurofibromatosis

Research Description
The Epstein laboratory is interested in molecular mechanisms of cardiovascular development and stem cell biology, and the implications of these mechanisms for understanding human disease. Transgenic and knockout mouse models are used. One area of interest is the developmental biology of neural crest. Neural crest cells are multipotent progenitors that give rise to nerve, bone, muscle, melanocytes and other cell types. Hence, they are an attractive model for studying stem cell biology. Neural crest defects are associated with congenital heart disease. Using Cre-lox approaches, we have demonstrated that neural crest cells in mammals give rise to the smooth muscle of the great vessels and portions of the outflow tract of the heart. Semaphorins, molecules that mediate repulsive axon guidance in the central nervous system, also mediate proper neural crest patterning and we have identified novel semaphorin pathways functional in the vasculature. Neural crest patterning is affected in mouse models of DiGeorge syndrome, a common human congenital condition associated with congenital heart disease. We have studied mouse models of DiGeorge syndrome including those with deletions or mutations in the Tbx1 transcription factor gene. Another human disorder associated with neural crest defects is Type I Neurofibromatosis. We have demonstrated that heart defects in Nf1 mutant mice are related to a function for this gene in endothelial cells which is distinct from its role in neural crest. Our lab is also interested in transcriptional regulation of cardiac muscle development and function. We have discovered an unusual homeobox gene that affects heart growth and function. Knockouts in mice and zebrafish have poorly formed hearts, and over-expression in adults causes adult cardiac hypertrophy and heart failure. Chromatin remodeling of cardiac-specific genes is affected. More recent work focuses on the role of chromatin remodeling, histone deacetylation (HDACs) and a small homeodomain protein called Hopx that is expressed in adult stem cells. We have developed several outstanding core facilities for histology, transgenics and mouse physiology to aid students and postdocs in accomplishing research goals and in accelerating productivity.

Rotation Projects
Opportunities are available to analyze transgenic and knockout mice that serve as models of congenital and adult heart disease. Analysis is at the whole animal level and at the molecular level. Specific projects involve the investigation of Pax3, Hopx, Tbx1 and Nf1 function in cardiovascular and neural crest tissues. Assays involving protein-protein interactions, transcriptional regulation and chromatin modification are commonly used. Projects are tailored to students' experience and interests.

Lab Members
Haig Aghajanian
Nikhita Bolar
Kurt Allen Engleka
Aidan Hancock
Deqiang Li
Jun Li
Feiyan Liu
Andrey Poleshko
Kelvin See
Cheryl Smith
Qiaohong Wang

Selected Publications

Ramjee, V., Li, D., Manderfield, L.J., Liu, F., Engleka, K.A., Aghajanian, H., Rodell, C.B., Lu, W., Ho, V., Wang, T., Li, L., Singh, A., Cibi, D.M., Burdick, J.A., Singh, M.K., Jain, R., Epstein, J.A.: Epicardial YAP/TAZ orchestrate an immunosuppressive response following myocardial infarction. J Clin Invest 127(3): 899-911, Mar 2017.

Loh, K.M., Chen, A., Koh, P.W., Deng, T.Z., Sinha, R., Tsai, J.M., Barkal, A.A., Shen, K.Y., Jain, R., Morganti, R.M., Shyh-Chang, N., Fernhoff, N.B., George, B.M., Wernig, G., Salomon, R.E., Chen, Z., Vogel, H., Epstein, J.A., Kundaje, A., Talbot, W.S., Beachy, P.A., Ang, L.T., Weissman, I.L.: Mapping the Pairwise Choices Leading from Pluripotency to Human Bone, Heart, and Other Mesoderm Cell Types. Cell 166(2): 451-67, July 2016.

Aghajanian, H., Cho, Y.K., Manderfieldm L.J., Herling, M.R., Gupta, M., Ho, V.C., Li, L., Degenhardt, K., Aharonov, A., Tzahor, E., Epstein, J.A.: Coronary vasculature patterning requires a novel endothelial ErbB2 holoreceptor. Nat Commun 7: 12038, June 2016.

Singh, A., Ramesh, S., Cibi1, D.M., Yun, L.S., Li, J. Li, L., J. Manderfield, L., Olson, E.N., Epstein, J.A. and Singh, M.K.: Hippo signaling mediators Yap and Taz are required in the epicardium for coronary vasculature development. Cell Reports 17(15): 1384-93, May 2016.

He, S., Mansour, M.R., Zimmerman, M.W., Ki, D.H., Layden, H.M., Akahane, K., Gjini, E., DeGroh, E.D., Perez-Atayde, A.R., Zhu, S., Epstein, J.A., Look, A.T.: Synergy between loss of NF1 and overexpression of MYCN in neuroblastoma is mediated by the GAP-related domain eLife 5:e14713, 2016.

Yzaguirre, A.D., Padmanabhan,A., de Groh, E.D., Engleka, K.A., Li, J., Speck, N.A., Epstein, J.A.: Loss of neurofibromin Ras-GAP activity enhances the formation of cardiac blood islands in murine embryos. eLife 4, Oct 2015.

Li, D., Takeda, N., Jain, R., Manderfield, L.J., Liu, F., Li, L., Anderson, S.A., Epstein, J.A.: Hopx distinguishes hippocampal from lateral ventricle neural stem cells. Stem Cell Res 15(3): 522-529, Oct 2015.

Manderfield, L.J., Aghajanian, H., Engleka, K.A., Lim, L.Y., Liu, F., Jain, R., Li, L., Olson, E.N., Epstein, J.A. : Hippo signaling is required for Notch-dependent smooth muscle differentiation of neural crest. Development 142(17): 2962-71, Sep 2015.

Jones, A., Opejin, A., Henderson, J.G., Gross, C., Jain, R., Epstein. J.A., Flavell, R.A., Hawiger, D.: Peripherally Induced Tolerance Depends on Peripheral Regulatory T Cells That Require Hopx To Inhibit Intrinsic IL-2 Expression. J Immunol 195(4): 1489-97, Aug 2015.

Han, S., Zhang, R., Jain, R., Shi, H., Zhang, L., Zhou, G., Sangwung, P., Tugal, D., Atkins, G.B., Prosdocimo, D.A., Lu, Y., Han, X., Tso, P., Liao, X., Epstein, J.A., Jain, M.K.: Corrigendum: Circadian control of bile acid synthesis by a KLF15-Fgf15 axis. Nat Commun 6: 8270, Aug 2015.

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Last updated: 10/03/2017
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