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.
Epigenomic analysis of TP53 activation in primary human fibroblasts. (A) The number of significantly enriched TP53 peaks (versus input, defined by MACS identified by ChIP-seq in IMR90 primary human lung fibroblasts after treatment with DMSO [blue] or nutlin [red]; 5 μM final in DMSO) for 6 h. (B) The percentage of TP53 peaks after nutlin treatment within varying distances to the nearest TSS of a RefSeq gene. (C,D) UCSC Genome Browser track view of TP53, RNA pol II, poly(A)+ selected RNA (mRNA), H3K4me1, H3K4me3, H4K16ac, and H3K27ac at the CDKN1A (C) and MDM2 (D) genes. Tracks for the DMSO and nutlin treatment condition are shown in blue and red, respectively, with regions of overlap depicted in black. The y-axis is scaled to the maximum intensity for each set of data. (E) Enrichment profiles (input subtracted) at TP53 peaks (TP53 peak center ±750 bp) in the DMSO (blue) and nutlin (red) treatment condition for TP53, RNA pol II, H3K4me1, H3K4me2, H3K4me3, H4K16ac, and H3K27ac.
RNA Binding to CBP Stimulates Histone Acetylation and Transcription
Disruption of TET2 promotes the therapeutic efficacy of CD19-targeted T cells
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.
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.
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.