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Jonathan A. Epstein, M.D.

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
Education:
A.B. (Biochemistry)
Harvard College, 1983.
M.D. (Medicine)
Harvard Medical School, 1988.
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Description of CVI Expertise

Executive Vice Dean and Chief Scientific Officer

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

Key Words: Cardiac development, Neural crest, Transcription, Hypertrophy, Pax, Neurofibromatosis.

The Epstein Lab studies molecular mechanisms of neural crest and cardiac development, with a particular interest in applying lessons learned from developmental models to the understanding and therapy of adult diseases. One area of interest relates to the role of the Pax3 transcription factor in neural crest cells. Neural crest can differentiate into a multitude of cell types including nerve, bone, vascular smooth muscle and melanocytes. Defects in neural crest, and mutations in Pax3, can lead to common forms of congenital heart disease. We have used mouse models to elucidate a molecular cascade involved in cardiac neural crest migration and differentiation, implicating members of the BMP, Notch, Semaphorin, myocardin and T-box families in this process. This work has direct relevance to the understanding of the genetic basis of congenital heart disease.

We have also used neural crest as a model of stem cell biology, and we have identified adult neural crest stem cells that reside in the hair follicle and give rise to regenerating melanocytes. Here, Pax3 plays a critical role both in determining cell-fate specification, and also in maintaining the undifferentiated stem cell phenotype until external signals, including induced by Wnt signals, trigger changes in transcriptional complexes and melanocyte differentiation.

Our studies have implicated important interactions between neural crest and other cell types, including vascular endothelium. We have discovered a novel member of the Plexin/Semaphorin family, PlexinD1, expressed by endothelial cells that is required for normal cardiovascular patterning. We have also demonstrated a critical endothelial function for the product of the type 1 Neurofibromatosis gene (NF1), which is a tumor suppressor gene mutated in von Recklinghausen Neurofibromatosis, a disease characterized by neural crest tumors and cardiovascular defects. This work has led to the appreciation for Ras signaling in epithelial-mesenchymal transformation in the heart and suggests that a common mechanism of cardiovascular defects in a series of childhood disorders, including Noonan’s syndrome and NF1. We are also using zebrafish models to exploit the ease of evaluation of the developing vasculature in our NF1 and Plexin studies.

Application of the elucidation of embryonic programs to adult disease is best exemplified by our work with a novel homeodomain factor called HOP. HOP is expressed early in cardiac development, but also functions in adult cardiac hypertrophy, and it is significantly down-regulated in human heart failure. HOP functions in association with HDAC2, a member of the histone deacetylase chromatin remodeling family. We have shown that HDAC inhibitors are potent anti-hypertensive agents, and our ongoing work suggests that HDAC2 is a critical molecular target of HDAC inhibitors in the heart. Our work suggests that HOP and HDAC2 regulate the fetal gene program during development, and again in the setting of adult disease when the fetal program is reactivated. Evaluation of these adult mouse models of heart disease is facilitated by imaging, microsurgery and invasive hemodynamic and electrophysiologic techniques that we have developed or refined to mimic all of the diagnostic tools available to the human adult cardiologist allowing us to develop new therapeutic targets for congestive heart failure.

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: 04/05/2017
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