Chromatin mechanisms of p53
TP53 is the most frequently mutated genes in human cancer and genetic evidence across biological taxa implicates TP53 as a master tumor suppressor gene. While wild type p53 is a potent tumor suppressor, certain p53 mutations result in oncogenic gain-of-function whereby mutant p53 instead drives oncogenesis. We are interested in two fundamental questions pertaining to the activity of wild-type and mutant p53. First, we are investigating how wild-type p53 exerts tumor suppressor activity in variable genomic and epigenomic context. Second, we are working to understand how mutant p53 functions from the chromatin to drive cancer progression. Our work on p53 spans multiple experimental paradigms, from traditional molecular and biochemical techniques to cutting-edge genetic and genomic technologies.
Epigenetic drivers of T cell dysfunction and epigenomics of CAR T therapy
A major contributor to cancer development and progression is failure of the immune system to recognize and clear tumor cells. Hence, therapies aimed at reinvigorating the immune system are a major area of translational research and currently show promising results in the clinic, such as chimeric antigen receptor (CAR) T therapy and PD-L1 blockade. A collaborative group of labs at Penn (Carl June, John Wherry, Joe Fraietta, and our lab) are striving to improve T cell functions for cancer treatment by 1) investigating epigenetic drivers and suppressors of T cell dysfunction (such as T cell exhaustion) in cancer and 2) profiling the epigenomic and transcriptomic landscape across CAR T therapy in cancer patients. Our goal is to broadly define the epigenetic landscape in immune and tumor cells prior to and following CAR T therapy and to utilize these epigenetic differences to boost immune response in patients. Meanwhile, we aim to interweave these lessons from the clinic research with studies that interrogate the mechanistic underpinnings of T cell dysfunction. With the overall objective of improving patient immune response, this study bridges basic, translational and clinical research to provide a rich understanding of the transcriptional and regulatory landscape of immune and tumor cells in response to immunotherapy.
An NK-like CAR T cell transition in CAR T cell dysfunction
Charly R. Good, M. Angela Aznar, Shunichiro Kuramitsu, Parisa Samareh, Sangya Agarwal, Greg Donahue, Kenichi Ishiyama, Nils Wellhausen, Austin K. Rennels, Yujie Ma, Lifeng Tian, Sonia Guedan, Katherine A. Alexander, Zhen Zhang, Philipp C. Rommel, Nathan Singh, Karl M. Glastad, Max W. Richardson, Keisuke Watanabe, Janos L. Tanyi, Mark H. O’Hara, Marco Ruella, Simon F. Lacey, Edmund K. Moon, Stephen J. Schuster, Steven M. Albelda, Lewis L. Lanier, Regina M. Young, Shelley L. Berger, Carl H. June, Cell, December 2021, 184(25): p. 6081-6100 e26, doi: 10.1016/j.cell.2021.11.016, PMID: 34861191
Genetics Meets Epigenetics in Treg Cells and Autoimmunity
Immunity. 2020 Jun 16;52(6):897-899. doi: 10.1016/j.immuni.2020.05.009. PMID: 32553177
Impaired Death Receptor Signaling in Leukemia Causes Antigen-Independent Resistance by Inducing CAR T-cell Dysfunction.
Cancer Discov. 2020 Apr;10(4):552-567. doi: 10.1158/2159-8290.CD-19-0813. Epub 2020 Jan 30. PMID: 32001516
TOX transcriptionally and epigenetically programs CD8+ T cell exhaustion.
Khan O, Giles JR, McDonald S, Manne S, Ngiow SF, Patel KP, Werner MT, Huang AC, Alexander KA, Wu JE, Attanasio J, Yan P, George SM, Bengsch B, Staupe RP, Donahue G, Xu W, Amaravadi RK, Xu X, Karakousis GC, Mitchell TC, Schuchter LM, Kaye J, Berger SL, Wherry EJ. (2019). Nature 2019 Jun 17.
p63 establishes epithelial enhancers at critical craniofacial development genes
Lin-Shiao E, Lan Y, Welzenbach J, Alexander KA, Zhang Z, Knapp M, Mangold E, Sammons M, Ludwig K, and Berger SL. (2019) Science Advances, May 1: 5.
Disruption of TET2 promotes the therapeutic efficacy of CD19-targeted T cells
Fraietta JA, Nobles CL, Sammons MA, Lundh S, Carty SA, Reich TJ, Cogdill AP, Morrissette JJD, DeNizio JE, Reddy S, Hwang Y, Gohil M, Kulikovskaya I, Nazimuddin F, Gupta M, Chen F, Everett JK, Alexander KA, Lin-Shiao E, Gee MH, Liu X, Young RM, Ambrose D, Wang Y, Xu J, Jordan MS, Marcucci KT, Levine BL, Garcia KC, Zhao Y, Kalos M, Porter DL, Kohli RM, Lacey SF, Berger SL, Bushman FD, June CH, Melenhorst JJ. (2018) Nature. 558(7709):307-312.
KMT2D regulates p63 target enhancers to coordinate epithelial homeostasis
Lin-Shiao E, Lan Y, Coradin M, Anderson A, Donahue G, Simpson CL, Sen P, Saffie R, Busino L, Garcia BA, Berger SL, Capell BC. (2018) Genes Dev. 32(2): 181-193.
RNA Binding to CBP Stimulates Histone Acetylation and Transcription
Bose DA, Donahue G, Reinberg D, Shiekhattar R, Bonasio R, Berger SL. (2017) Cell. 168(1-2):135-149.e22.
Epigenetic stability of exhausted T cells limits durability of reinvigoration by PD-1 blockade
Pauken KE, Sammons MA, Odorizzi PM, Manne S, Godec J, Khan O, Drake AM, Chen Z, Sen DR, Kurachi M, Barnitz RA, Bartman C, Bengsch B, Huang AC, Schenkel JM, Vahedi G, Haining WN, Berger SL, Wherry EJ. (2016) Science. 354(6316):1160-1165.
Lysine methylation represses p53 activity in teratocarcinoma cancer cells.
Zhu J, Dou Z, Sammons MA, Levine AJ, Berger SL. (2016) PNAS. 113(35):9822-7
Gain-Of-Function p53 Mutants Co-Opt Epigenetic Pathways To Drive Cancer Growth
Zhu J, Sammons MA, Donahue G, Dou Z, Vedadi M, Getlik M, Barsyte-Lovejoy D, Al-Awar R, Katona BW, Shilatifard A, Huang J Hua X, Arrowsmith CH, and Berger SL. (2015) Nature. 525(7568):206-11.
TP53 Engagement With The Genome Occurs In Distinct Local Chromatin Environments Via Pioneer Factor Activity
Sammons MA, Zhu J, Drake AM, Berger SL. (2015) Genome Research. 25(2):179-88.