p53 is the most commonly mutated gene in human cancer. The p53 protein is a stress- and DNA damage-responsive transcriptional activator that binds to DNA to activate cell protective pathways, including cell cycle arrest, DNA repair, and apoptosis. The majority of p53 mutations in cancer inactivate the tumor suppressor via disruption of p53 DNA binding and hence transcriptional activation activity. The p53 protein is subject to numerous regulatory post-translational modifications, and additionally, the p53 transcription factor binds to target genes to recruit chromatin and histone modifiers as a key mechanism in gene activation. Given p53's normal role in chromatin regulation, p53 mutations and alterations in oncogenesis likely impair epigenetic pathways targeted by p53. Further elucidation of interactions between p53 and chromatin will therefore illuminate cancerous disruptions. Our recent published and preliminary data explore key mechanisms in the function and regulation of p53 as a transcriptional activator and regulating chromatin, and we will clarify these pathways in the proposed studies. First, we find that certain well-known p53 gain-of-function substitution mutations bind to and up-regulate an epigenetic gene signature, which, in turn, modifies histones to activate downstream ras/rho growth pathways. We plan to critically evaluate the mechanism and importance of this epigenetic signature in human tumor-derived cell lines bearing p53 gain-of-function substitutions and with related in vivo mouse models. Second, teratocarcinoma tumors paradoxically express high levels of wild type inactive p53; we show p53 in these cancers is decorated with elevated levels of repressive lysine methylation. In the proposed research, we will determine whether the methylation is crucial to inhibition of wild type p53 in teratocarcinomas. Third, we find that, beyond well-known p53 binding to promoters of target genes, surprisingly, the majority of stress- inducible p53 binding sites are distal to genes, appearing to be at enhancers. In the proposed studies we will address the interplay between p53 and certain histone modifiers in establishing enhancer function and gene activation. Fourth, by way of a high throughput si/shRNA screen for epigenetic regulators of p53-mediated gene activation, we observe an association of p53 with factors that mediate large-scale chromatin architecture. We will investigate direct roles of cohesion and CTCF in regulating the p53 transcriptional response via regulation of specific chromatin looping and architecture. Results from these studies will elucidate epigenetic mechanisms regulating p53 function, will explore involvement of these epigenetic pathways in p53 function in vivo and in cancer, and will launch investigation of tailored epigenetic therapies to ameliorate specific p53-driven cancer phenotypes.
p53, the most commonly mutated gene in human cancer, functions to activate gene expression and this mechanism is typically disrupted in tumors. Our work will elucidate normal and disease-altered mechanisms in gene regulatory and epigenetic pathways governed by p53. Our results will launch investigation of tailored epigenetic therapies to ameliorate specific p53-driven cancer phenotypes.
| Lin-Shiao, Enrique; Lan, Yemin; Coradin, Mariel et al. (2018) KMT2D regulates p63 target enhancers to coordinate epithelial homeostasis. Genes Dev 32:181-193 |
| Dou, Zhixun; Berger, Shelley L (2018) Senescence Elicits Stemness: A Surprising Mechanism for Cancer Relapse. Cell Metab 27:710-711 |
| Bose, Daniel A; Donahue, Greg; Reinberg, Danny et al. (2017) RNA Binding to CBP Stimulates Histone Acetylation and Transcription. Cell 168:135-149.e22 |
| Bonini, Nancy M; Berger, Shelley L (2017) The Sustained Impact of Model Organisms-in Genetics and Epigenetics. Genetics 205:1-4 |
| Dou, Zhixun; Ghosh, Kanad; Vizioli, Maria Grazia et al. (2017) Cytoplasmic chromatin triggers inflammation in senescence and cancer. Nature 550:402-406 |
| Levine, Arnold J; Berger, Shelley L (2017) The interplay between epigenetic changes and the p53 protein in stem cells. Genes Dev 31:1195-1201 |
| Bose, Daniel A; Berger, Shelley L (2017) eRNA binding produces tailored CBP activity profiles to regulate gene expression. RNA Biol 14:1655-1659 |
| Pauken, Kristen E; Sammons, Morgan A; Odorizzi, Pamela M et al. (2016) Epigenetic stability of exhausted T cells limits durability of reinvigoration by PD-1 blockade. Science 354:1160-1165 |
| Zhu, Jiajun; Dou, Zhixun; Sammons, Morgan A et al. (2016) Lysine methylation represses p53 activity in teratocarcinoma cancer cells. Proc Natl Acad Sci U S A 113:9822-7 |
| Sammons, Morgan A; Zhu, Jiajun; Berger, Shelley L (2016) A Chromatin-Focused siRNA Screen for Regulators of p53-Dependent Transcription. G3 (Bethesda) 6:2671-8 |
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