JONATHAN A. EPSTEIN, M.D.

Executive Vice Dean and Chief Scientific Officer
William Wikoff Smith Professor of Medicine

Lab Webpage

https://www.pennmedicine.org/departments-and-centers/penn-cardiovascular-institute/members/principal-investigators/epstein-lab

Faculty Webpage

https://www.med.upenn.edu/apps/faculty/index.php/g275/p12834

Contact Information

University of Pennsylvania
Perelman School of Medicine
602 PCAM South Expansion
3400 Civic Center Blvd.
Philadelphia, PA 19104
Office: 215-898-8731
Fax: 215-573-2030
epsteinj@pennmedicine.upenn.edu

Publication Links

Research Interest

The Epstein Laboratory studies cardiovascular development, the genetics of congenital heart disease and cardiovascular regenerative and stem cell biology. The lab has a long-standing interest in congenital heart defects involving the outflow tract of the heart, the role of neural crest, the epicardium and the second heart field. More recent areas of focus include the cardiac inflow tract and the pulmonary veins and the origin of anomalous pulmonary venous return. Other areas of interest include the factors and genes involved in progressive lineage restriction of cardiac progenitor cells and the role of epigenetics in progenitor cell expansion and differentiation. The lab is also interested in the implications of these studies for the development of new therapies for adult cardiovascular disorders including heart failure and arrhythmia. Specific projects have focused on the role of Notch and Wnt in cardiac progenitors, semaphorin signaling in the developing vasculature, the function of a novel homeobox gene Hopx and histone deacetylases in stem cells and the heart, and the role of the type I Neurofibromatosis gene (Nf1) in mouse and zebrafish cardiac development.

Contribution to Science

We have elucidated the role of epigenetics in heart development and we have applied this knowledge to explore novel therapies for adult cardiac disease including ischemia-reperfusion and congestive heart failure.  In particular, we demonstrated that histone deacetylase inhibitors can prevent pathologic cardiac hypertrophy, which was counter to the prevailing dogma at the time.

  • Trivedi CM, Zhu W, Wang Q, Jia C, Kee HJ, Li L, Hannenhalli S, Epstein JA. Hopx and Hdac2 interact to modulate Gata4 acetylation and embryonic cardiac myocyte proliferation. Developmental cell. 2010;19(3):450-9. PMCID: PMC2947937
  • Trivedi CM, Luo Y, Yin Z, Zhang M, Zhu W, Wang T, Floss T, Goettlicher M, Noppinger PR, Wurst W, Ferrari VA, Abrams CS, Gruber PJ, Epstein JA. Hdac2 regulates the cardiac hypertrophic response by modulating Gsk3 beta activity. Nature medicine. 2007;13(3):324-31.
  • Kook H, Lepore JJ, Gitler AD, Lu MM, Wing-Man Yung W, Mackay J, Zhou R, Ferrari V, Gruber P, Epstein JA. Cardiac hypertrophy and histone deacetylase-dependent transcriptional repression mediated by the atypical homeodomain protein Hop. The Journal of clinical investigation. 2003;112(6):863-71. PMCID: PMC193673.
  • Chen F, Kook H, Milewski R, Gitler AD, Lu MM, Li J, Nazarian R, Schnepp R, Jen K, Biben C, Runke G, Mackay JP, Novotny J, Schwartz RJ, Harvey RP, Mullins MC, Epstein JA. Hop is an unusual homeobox gene that modulates cardiac development. Cell. 2002;110(6):713-23.

My laboratory has contributed to our understanding of how the neural crest influences cardiac development and to the embryologic and genetic basis of congenital heart disease.Neural crest contribution to the heart was described in the early 1980s by Kirby and colleagues, and our laboratory extended these observations to mammalian systems, performed genetic fate-mapping in mouse models, identified candidate genes for congenital heart defects and described molecular pathways including Notch, Fgf, Wnt and Hippo that regulate cross-talk between neural crest, endothelium and second heart field derivatives in the heart.

  • Manderfield LJ, Engleka KA, Aghajanian H, Gupta M, Yang S, Li L, Baggs JE, Hogenesch JB, Olson EN, Epstein JA. Pax3 and hippo signaling coordinate melanocyte gene expression in neural crest. Cell reports. 2014;9(5):1885-95. PMCID: PMC4267159.
  • Manderfield LJ, High FA, Engleka KA, Liu F, Li L, Rentschler S, Epstein JA. Notch activation of Jagged1 contributes to the assembly of the arterial wall. Circulation. 2012;125(2):314-23. PMCID: PMC3260393.
  • Katz TC, Singh MK, Degenhardt K, Rivera-Feliciano J, Johnson RL, Epstein JA, Tabin CJ. Distinct compartments of the proepicardial organ give rise to coronary vascular endothelial cells. Developmental cell. 2012;22(3):639-50. PMCID: PMC3306604.
  • de la Pompa JL, Epstein JA. Coordinating tissue interactions: Notch signaling in cardiac development and disease. Developmental cell. 2012;22(2):244-54. PMCID: PMC3285259.

We described the molecular basis for cardiovascular manifestations in Type 1 Neurofibromatosis using mouse and zebrafish models, including valvular pulmonic stenosis, endothelial defects and cardiac hypertrophy.We generated a zinc-finger knockout of the Nf1 genes in zebrafish, and demonstrated behavioral defects amenable to small molecule drug screening.

  • Wolman MA, de Groh ED, McBride SM, Jongens TA, Granato M, Epstein JA. Modulation of cAMP and ras signaling pathways improves distinct behavioral deficits in a zebrafish model of neurofibromatosis type 1. Cell reports. 2014;8(5):1265-70.
  • Shin J, Padmanabhan A, de Groh ED, Lee JS, Haidar S, Dahlberg S, Guo F, He S, Wolman MA, Granato M, Lawson ND, Wolfe SA, Kim SH, Solnica-Krezel L, Kanki JP, Ligon KL, Epstein JA, Look AT. Zebrafish neurofibromatosis type 1 genes have redundant functions in tumorigenesis and embryonic development. Disease models & mechanisms. 2012;5(6):881-94. PMCID: PMC3484870.
    Ismat FA, Xu J, Lu MM, Epstein JA. The neurofibromin GAP-related domain rescues endothelial but not neural crest development in Nf1 mice. The Journal of clinical investigation. 2006;116(9):2378-84. PMCID: PMC1533876.
  • Gitler AD, Zhu Y, Ismat FA, Lu MM, Yamauchi Y, Parada LF, Epstein JA. Nf1 has an essential role in endothelial cells. Nature genetics. 2003;33(1):75-9. PMCID: PMC3079412.

We were among the first to show that guidance molecules known to regulate the migration of axons in the central nervous system can also regulate angiogenesis and cardiac development.  We have shown that members of the semaphorin and plexin families help to pattern the outflow tract of the heart, the pulmonary veins and coronary arteries, and the peripheral vasculature.

  • Epstein JA, Aghajanian H, Singh MK. Semaphorin signaling in cardiovascular development. Cell metabolism. 2015;21(2):163-73.
  • Aghajanian H, Choi C, Ho VC, Gupta M, Singh MK, Epstein JA. Semaphorin 3d and semaphorin 3e direct endothelial motility through distinct molecular signaling pathways. The Journal of biological chemistry. 2014;289(26):17971-9. PMCID: PMC4140303.
  • Degenhardt K, Singh MK, Aghajanian H, Massera D, Wang Q, Li J, Li L, Choi C, Yzaguirre AD, Francey LJ, Gallant E, Krantz ID, Gruber PJ, Epstein JA. Semaphorin 3d signaling defects are associated with anomalous pulmonary venous connections. Nature medicine. 2013;19(6):760-5. PMCID: PMC3746328.
  • Gitler AD, Lu MM, Epstein JA. PlexinD1 and semaphorin signaling are required in endothelial cells for cardiovascular development. Developmental cell. 2004;7(1):107-16.

I have contributed to the dissemination of scientific knowledge across disciplines and to the public, as evidenced by service as President of the American Society for Clinical Investigation, Deputy Editor of the Journal of Clinical Investigation, contributions to the Institute of Medicine, and author of numerous scholarly commentaries on public policy and health care.

My dedication to community service in academic medicine is evidenced by my service as chairman of an NIH study section (CDD) and multiple roles on study sections at the NIH, DOD and AHA, and as a frequent journal reviewer, member of editorial boards, member of NHLBI Council and co-chair of NHLBI strategic planning.

  • Roger VL, Boerwinkle E, Crapo JD, Douglas PS, Epstein JA, Granger CB, Greenland P, Kohane I, Psaty BM. Strategic transformation of population studies: recommendations of the working group on epidemiology and population sciences from the National Heart, Lung, and Blood Advisory Council and Board of External Experts. American journal of epidemiology. 2015;181(6):363-8. PMCID: PMC4375403.
  • Epstein JA. Enhancing discovery and saving money with MERIT. The Journal of clinical investigation. 2011;121(4):1226. PMCID: PMC3069800.
  • Epstein JA. Politicizing NIH funding: a bridge to nowhere. The Journal of clinical investigation. 2011;121(9):3362-3. PMCID:PMC3171103.
  • Epstein JA, Turka LA, Birnbaum M, Koretzky G. The physician’s voice in the health care debate. The Journal of clinical investigation. 2009;119(10):2846. PMCID: PMC2752093.