About

Shelley L. Berger, Ph.D., is the Daniel S. Och University Professor and a Presidential Appointment at the University of Pennsylvania. She serves as the Director of the Epigenetics Institute at the Perelman School of Medicine and is a Co-Director of the Tumor Biology Program at the Abramson Cancer Center. Her research focuses on epigenetics and chromatin structure/function in genomic regulation, particularly the post-translational modifications of histones and transcription factors. Her work investigates chromatin regulation of transcription, neuroepigenetics, behavioral epigenetics, and chromatin regulation in disease contexts such as cancer, aging, and neurodegeneration. Berger's research emphasizes understanding how chemical modifications of histones influence genome functions like gene expression, DNA replication, and DNA repair, and how these modifications are involved in normal development and disease states. She has contributed to the understanding of histone modifications, enzyme recruitment, and the regulation of non-histone proteins like p53, with a focus on how these modifications can activate or repress protein functions. Her current research aims to elucidate the role of epigenetic modifications in cellular processes such as gametogenesis, viral latency, aging, and cancer, including studies on chromatin changes during replicative aging and the broader implications of epigenetics in medicine.

Research topics

• Biology
• Genetics
• Computational biology
• Cell biology
• Medicine
• Immunology
• Bioinformatics
• Biochemistry

Selected publications

• Figure S6 from Type I Interferon Signaling via the EGR2 Transcriptional Regulator Potentiates CAR T Cell–Intrinsic Dysfunction

  2025-12-11

  articleOpen access

  <p>Pathways regulated by EGR2 in CD8+ CAR T-cells. (A-C) Top pathways differentially expressed in EGR2 knockout CD8+ CAR-T cells compared to AAVS1 knockout CAR T-cells. Libraries used in this enrichment analysis: A, Reactome 2016. B, NCI-Nature Pathway Interaction Database 2015. C, ARCHS4 transcription factor (TF) co-expression.</p>

  PublisherOA PDFDOI

• Figure S4 from Type I Interferon Signaling via the EGR2 Transcriptional Regulator Potentiates CAR T Cell–Intrinsic Dysfunction

  2025-12-11

  articleOpen access

  <p>Marker gene expression in CAR T-cell clusters. A, Uniform manifold approximation and projection (UMAP) plot of AAVS1 and EGR2 knockout (KO) CAR T-cell samples is shown. B, UMAP plots showing expression levels of CD4 and CD8. C, Violin plot depicting expression of cluster-defining markers in CD4+ T-cells. D, Differentially expressed genes in IL7R+ versus CTLA4+ CD4+ T-cells. E, Violin plots showing expression levels of cluster-defining markers in CD8+ T-cells. F, Heatmap displaying differentially expressed genes between CD8+ cell clusters. G, Cell cycle scores mapped on UMAP plots.</p>

  PublisherDOI

• Figure S11 from Type I Interferon Signaling via the EGR2 Transcriptional Regulator Potentiates CAR T Cell–Intrinsic Dysfunction

  2025-12-11

  articleOpen access

  <p>Analysis of survival outcomes and EGR2 gene expression in CD19 CAR T-cell products. The figure presents the P values and hazard ratio of different EGR2 molecular marker stratification points in relation to A, overall survival and B, event-free survival The black arrows indicate the stratification points used in the study. C, EGR2-targeted gene expression scores in CD19 CAR T-cell products from responders and non-responders in pediatric ALL. D, Summary of how EGR2 regulates resistance to CAR T-cell therapy through the type I IFN pathway.</p>

  PublisherOA PDFDOI

• Figure S5 from Type I Interferon Signaling via the EGR2 Transcriptional Regulator Potentiates CAR T Cell–Intrinsic Dysfunction

  2025-12-11

  articleOpen access

  <p>Gene expression and pathway enrichment analysis of CD8+ T cell clusters. A, Heatmap showing differentially expressed genes between memory-like KLF2+ and exhausted-like MKI67+ CD8+ T-cells. Gene signature scores related to cell cycle and clinical response are indicated on the top bars. B, Top downregulated GO biological processes in EGR2 compared to AAVS1 knockout CAR T-cells.</p>

  PublisherDOI

• Table S2 from Type I Interferon Signaling via the EGR2 Transcriptional Regulator Potentiates CAR T Cell–Intrinsic Dysfunction

  2025-12-11

  articleOpen access

  <p>Genes deferentially expressed in EGR2 compared to AAVS1 knockout CD8+ CAR T-cells. The corresponding log2 fold change values and statistical significance are provided for the listed genes.</p>

  PublisherDOI

• Clinical and molecular dissection of CAR T cell resistance in pancreatic cancer

  Cell Reports Medicine · 2025-08-18 · 8 citations

  articleOpen access

  phenotype. Single knockout of ID3 or SOX4 enhances efficacy in xenograft models, though with donor-dependent variability. However, single-knockout cells eventually fail. Conversely, ID3 and SOX4 double-knockout CAR T cells exhibit prolonged relapse-free survival, demonstrating a sustained therapeutic effect and a potential avenue for engineering more potent CAR T cells in PDAC. This study was registered at ClinicalTrials.gov (NCT03323944).

  PublisherOA PDFDOI

• Figure S9 from Type I Interferon Signaling via the EGR2 Transcriptional Regulator Potentiates CAR T Cell–Intrinsic Dysfunction

  2025-12-11

  articleOpen access

  <p>Epigenetic remodeling of CAR T-cells by EGR2 knockout and effect of type I IFN signaling on the development of memory and exhaustion. A, Volcano plots showing differentially accessible chromatin regions within genes between KLF2+ and MKI67+ CD8+ T-cells. B, Volcano plots depicting differentially accessible chromatin regions within genes between EGR2 and AAVS1 knockout (KO) CD8+ CAR T-cells. C, Representative contour plots showing frequencies of TIM3- and LAG3-expressing CD8+ CAR-T cells after exposure to IFNβ (1ng/mL) following chronic CAR stimulation. D, Proportions of CD27+ (left) or CD62L+ (right) CD8+ CAR-T cells after exposure to IFNβ. E, Representative contour plots showing frequencies of CD45RO+CD27+ CD8+ CAR-T cells after IFNAR blockade (Anifrolumab, 1µg/mL) during chronic antigen stimulation. F, Frequencies of TIM3+LAG3+ CD8+ CAR-T cells after IFNAR blockade. G, Cytolytic capacity of CAR T-cells as measured by normalized cell index kinetics using the xCELLigence real-time cytotoxicity assay following chronic stimulation with target cancer cells in the setting of either IFNβ or IFNAR blockade. H, Normalized cell index at 75 hours after challenge with target cancer cells. All experiments were conducted using healthy donor T-cells from independent donors (Mann-Whitney test, n = 4). *P < 0.05, *P < 0.01, ***P < 0.001, ns.: not significant.</p>

  PublisherOA PDFDOI

• SIRT7 regulates NUCKS1 chromatin binding to elicit metabolic and inflammatory gene expression in senescence and liver aging

  Molecular Cell · 2025-06-01 · 8 citations

  articleSenior authorCorresponding
  PublisherDOI

• Deciphering the role of histone modifications in memory and exhausted CD8 T cells

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-04-22

  preprintOpen accessCorresponding

  ABSTRACT Exhausted CD8 T cells (T EX ) arising during chronic infections and cancer have reduced functional capacity and limited fate flexibility that prevents optimal disease control and response to immunotherapies. Compared to memory (T MEM ) cells, T EX have a unique open chromatin landscape underlying a distinct gene expression program. How T EX transcriptional and epigenetic landscapes are regulated through histone post-translational modifications (hPTMs) remains unclear. Here, we profiled key activating (H3K27ac and H3K4me3) and repressive (H3K27me3 and H3K9me3) histone modifications in naive CD8 T cells (T N ), T MEM and T EX . We identified H3K27ac-associated super-enhancers that distinguish T N , T MEM and T EX , along with key transcription factor networks predicted to regulate these different transcriptional landscapes. Promoters of some key genes were poised in T N , but activated in T MEM or T EX whereas other genes poised in T N were repressed in T MEM or T EX , indicating that both repression and activation of poised genes may enforce these distinct cell states. Moreover, narrow peaks of repressive H3K9me3 were associated with increased gene expression in T EX , suggesting an atypical role for this modification. These data indicate that beyond chromatin accessibility, hPTMs differentially regulate specific gene expression programs of T EX compared to T MEM through both activating and repressive pathways.

  PublisherOA PDFDOI

• Figure S2 from Type I Interferon Signaling via the EGR2 Transcriptional Regulator Potentiates CAR T Cell–Intrinsic Dysfunction

  2025-12-11

  articleOpen access

  <p>Impact of EGR2 knockout on CD8+/CD4+ ratio and Th2 cytokine production in the setting of chronic tumor antigen stimulation. A, Comparison of CD8+/CD4+ ratio in control and EGR2 knockout (KO) CAR T-cells after chronic CAR stimulation. B, Th2 cytokine production by control and EGR2 KO CAR T-cells after 24 hours of CAR stimulation (Mann-Whitney test, n = 4). All experiments were performed using T-cells from three independent healthy donors. Panel B is representative data from one donor. *P < 0.05, **P < 0.01, ***P < 0.001, ns: not significant.</p>

  PublisherOA PDFDOI

Recent grants

• The metabolic-epigenetic axis in memory

  NIH · $2.2M · 2019–2025

• Epigenetic regulation by tumor suppressor p53

  NIH · $7.8M · 1999–2024

• NIH Grant R01NS078283

  NIH · $3.3M · 2018

• NIH Grant R01GM055360

  NIH · $5.7M · 2016

• Epigenetics of Aging and Age-Associated Diseases

  NIH · $4.5M · 2008–2023

Frequent coauthors

• Noelle V. Frey

  California University of Pennsylvania

  119 shared

• Sierra M. Collins

  100 shared

• Joseph A. Fraietta

  University of Pennsylvania

  99 shared

• In-Young Jung

  Korea University

  96 shared

• Robert L. Bartoszek

  96 shared

• Andrew J. Rech

  95 shared

• Frederic D. Bushman

  94 shared

• J.K. Everett

  93 shared

Labs

• Berger LabPI

Education

• Postdoctoral (Genetics & Molecular Biology)

  Massachusetts Institute of Technology

  1993

• Postdoctoral (Molecular Biology)

  Harvard University

  1989

• B.S. (Biology)

  University of Michigan

  1982

Awards & honors

• Penn Integrates Knowledge Presidential Appointment, Universi…