Cancer

Cancer

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.

Publications

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.

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

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.