About

Jonathan A. Epstein, M.D., is the Robert G. Dunlop Professor and Dean of the Perelman School of Medicine at the University of Pennsylvania. He also serves as the Executive Vice President of the University of Pennsylvania for the Health System. His research expertise focuses on the epigenetic regulation of stem cell biology, developmental biology, and cardiovascular medicine. His laboratory investigates the molecular mechanisms of cardiovascular development and stem cell biology, with a longstanding history of studying the genetic causes of congenital heart disease and mechanisms of cell fate determination. The lab combines biochemistry, cell biology, and genomics to explore how the three-dimensional organization of chromatin in the nucleus contributes to cell identity and how protein complexes tether regions of the genome to the nuclear periphery to regulate gene programs, including those defining cardiac cell types. Recent work emphasizes the role of histone deacetylases in cardiac development and adult heart function, as well as the regulation of gene expression through interactions between the nuclear lamina and chromatin. Epstein's lab has also discovered the tumor suppressor and stem cell gene Hopx and continues to study its role in the heart and in tissue-specific adult resident stem cells across various tissues. Additionally, his research includes engineering immune cells for potential treatments of cardiovascular disorders.

Research topics

• Biology
• Bioinformatics
• Internal medicine
• Medicine
• Immunology
• Oncology
• Intensive care medicine

Selected publications

• Hopx(+) optic nerve head-astrocytes counter neuronal stress and glaucoma damage

  Proceedings of the National Academy of Sciences · 2026-04-27

  articleOpen access

  Retinal ganglion cell (RGC) axons form the optic nerve (ON). Numerous age-related ON diseases, including glaucoma, the second most common cause of worldwide blindness, result from multiple RGC stressors. Nearly all ON astrocytes in the optic nerve head (ONH): the junctional region between the ON and the retina in young-adult rodents expresses the homeodomain only (Hopx) protein. Hopx(+) ONH astrocytes are depleted during aging. ONH primary cultures which include Hopx(+) astrocytes secrete extracellular vesicles (ONH-EVs) which selectively enhance RGC survival and neurite extension in culture, while extracellular vesicles (EVs) secreted from distal ON cultures lacking Hopx(+) astrocytes do not. ONH-EVs also enhance RGC survival in vivo in a rodent model of glaucoma. Combining rat ONH single-cell (scRNA-seq) sequencing with EV proteomic analysis, we identified ONH-Hopx(+) astrocyte secreted factors. We interrogated the online Broad institute scRNA-seq database for rat RGC gene expression in control animals and following rodent ON crush, an RGC stress model, to correlate ONH-astrocyte secreted factors with RGC gene expression changes. Following stress, RGCs upregulate the complementary pathways involving Hopx(+) astrocytic-associated factors, suggesting reciprocal communication. Using a highly selective transgenic Hopx-cre ONH knockdown strategy, we demonstrate that eliminating Hopx(+) astrocytes also results in upregulation of RGC stress responses. Our results implicate age-related loss of young ONH-astrocytes as a crucial factor in the development of age-related optic nerve diseases, and discuss replacing ONH associated factors as a paradigm shift for ON disease treatment.

  PublisherDOI

• In vivo anti-FAP CAR T therapy reduces fibrosis and restores liver homeostasis in metabolic dysfunction-associated steatohepatitis

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-02-27 · 8 citations

  preprintOpen access

  In this study, we aimed to determine the efficacy of in vivo chimeric antigen receptor (CAR) T cell therapy, generated by targeted lipid nanoparticles (t-LNPs), as an anti-fibrotic in metabolic dysfunction-associated steatotic liver disease. Hepatic fibrosis is a key predictor of mortality in liver disease, driven by fibrogenic hepatic stellate cells (HSCs). In heart, chimeric antigen receptor (CAR) T cells targeting fibroblast activation protein alpha (FAP) reduce murine cardiac fibrosis. However, the value of this approach in liver is unknown. We explored the anti-fibrotic potential of in vivo-generated anti-FAP CAR T cells in metabolic dysfunction-associated steatohepatitis (MASH), a highly prevalent disease with no approved anti-fibrotic therapies. We first established that FAP expression in both human and murine MASH is specific to HSCs. We then used flow cytometry, Sirius Red morphometry, digital pathology analysis, and single nuclear RNA-sequencing to assess the impact of anti-FAP CAR T cell therapy on murine MASH. Anti-CD5 targeted-LNPs carrying anti-FAPCAR mRNA generate activated, transient anti-FAP CAR T cells, which significantly reduced fibrosis by depleting pro-fibrogenic HSCs, and by modulating immune cells, endothelial cells and hepatocytes in a non-cell autonomous manner to mitigate inflammation and restore hepatic homeostasis. These findings reinforce the potential of in vivo CAR T therapy to attenuate a highly morbid and pervasive liver disease through integrated, multicellular salutary effects. One Sentence Summary: RNA-based treatment transiently reprograms immune cells to target scar-forming cells in fatty liver disease, thus improving liver health overall.

  PublisherOA PDFDOI

• Reorganization of H3K9me2-modified chromatin regions during mouse embryonic development

  Developmental Biology · 2025-09-17 · 1 citations

  articleOpen accessCorresponding
  PublisherOA PDFDOI

• Immunomodulatory Therapy for Ischemic Heart Disease

  Circulation · 2024-09-23 · 12 citations

  reviewOpen access

  Ischemic heart disease is a leading cause of death worldwide, manifested clinically as myocardial infarction (and ischemic cardiomyopathy. Presently, there exists a notable scarcity of efficient interventions to restore cardiac function after myocardial infarction. Cumulative evidence suggests that impaired tissue immunity within the ischemic microenvironment aggravates cardiac dysfunction, contributing to progressive heart failure. Recent research breakthroughs propose immunotherapy as a potential approach by leveraging immune and stroma cells to recalibrate the immune microenvironment, holding significant promise for the treatment of ischemic heart disease. In this Primer, we highlight three emerging strategies for immunomodulatory therapy in managing ischemic cardiomyopathy: targeting vascular endothelial cells to rewire tissue immunity, reprogramming myeloid cells to bolster their reparative function, and utilizing adoptive T cell therapy to ameliorate fibrosis. We anticipate that immunomodulatory therapy will offer exciting opportunities for ischemic heart disease treatment.

  PublisherOA PDFDOI

• HPR133 Clinical Benefits of the Accelerated Approval Program in Oncology

  Value in Health · 2024-06-01

  articleOpen accessSenior author
  PublisherOA PDFDOI

• Linking immune modulation to cardiac fibrosis

  Nature Cardiovascular Research · 2024-04-01 · 8 citations

  articleOpen access
  PublisherOA PDFDOI

• Epigenetics

  Advances in experimental medicine and biology · 2024-01-01 · 10 citations

  reviewSenior author
  PublisherDOI

• From Improvised to Intentional: Re-Imagining the Physician-Scientist Career Path

  JCI Insight · 2024-04-13

  articleOpen access

  The physician-scientist career has historically progressed through individual persistence and improvisation, as physician-scientists have navigated the demands of clinical practice combined with biomedical research without a clearly structured path.While this approach has sustained the

  PublisherOA PDFDOI

• Growth factor–induced activation of MSK2 leads to phosphorylation of H3K9me2S10 and corresponding changes in gene expression

  Science Advances · 2024-03-13 · 6 citations

  articleOpen accessSenior authorCorresponding

  Extracellular signals are transmitted through kinase cascades to modulate gene expression, but it remains unclear how epigenetic changes regulate this response. Here, we provide evidence that growth factor-stimulated changes in the transcript levels of many responsive genes are accompanied by increases in histone phosphorylation levels, specifically at histone H3 serine-10 when the adjacent lysine-9 is dimethylated (H3K9me2S10). Imaging and proteomic approaches show that epidermal growth factor (EGF) stimulation results in H3K9me2S10 phosphorylation, which occurs in genomic regions enriched for regulatory enhancers of EGF-responsive genes. We also demonstrate that the EGF-induced increase in H3K9me2S10ph is dependent on the nuclear kinase MSK2, and this subset of EGF-induced genes is dependent on MSK2 for transcription. Together, our work indicates that growth factor-induced changes in chromatin state can mediate the activation of downstream genes.

  PublisherOA PDFDOI

• Emerging mRNA therapies for cardiac fibrosis

  American Journal of Physiology-Cell Physiology · 2023-12-04 · 14 citations

  editorialOpen accessSenior author

  Cardiac fibrosis has few specific interventions available for effective treatment. mRNA encapsulated in lipid nanoparticles could provide a novel solution for treating cardiac fibrosis. This AJP perspective discusses what possible strategies could rely on this technology, from in vivo-produced CAR T cells that kill pathological fibroblasts to in vivo-produced T regulatory cells that dampen the concomitant profibrotic inflammatory cells contributing to remodeling, directly targeting fibroblasts and eliminating them or silencing profibrotic pathways.

  PublisherOA PDFDOI

Recent grants

• NIH Grant R01DK057050

  NIH · $940k · 2004

• NIH Grant R01DK059176

  NIH · $832k · 2003

• NIH Grant R01HL071546

  NIH · $4.9M · 2018

• Cardiac lineage determination and nuclear architecture

  NIH · $5.8M · 2018–2024

• NIH Grant R01HL131611

  NIH · $804k · 2020

Frequent coauthors

• Min Lü

  Ruijin Hospital

  111 shared

• Igor B. Dawid

  Eunice Kennedy Shriver National Institute of Child Health and Human Development

  109 shared

• Neil A. Hukriede

  University of Pittsburgh

  108 shared

• Mario Chevrette

  McGill University

  106 shared

• W. Brad Barbazuk

  University of Florida

  106 shared

• Stephen L. Johnson

  Transylvania University

  106 shared

• John D. McPherson

  University of California, Davis

  106 shared

• Marc Ekker

  University of Ottawa

  106 shared

Labs

• Epstein LaboratoryPI