p16 Epimutation: Function in Tumorigenesis and As A Target for Cancer Therapy
p16 (or p16INK4a) is a tumor suppressor gene that regulates cell cycle. p16 epimutation - inactivation of p16 by promoter DNA methylation - is one of the most common epigenetic events in human colorectal cancer. We published the first mouse model of targeted p16 promoter methylation (J Clin Invest. 2014; 124:3708). Using these mice, we demonstrate that engineered p16 epimutation drives spontaneous tumor development. Recently, our studies have revealed that p16 epimutation operates synergistically with mutant K-ras and Apc(Min) to promote lung and colon tumor progression. Our overall goals are to understand epigenetic causality of human cancers and to identify epigenetic vulnerabilities that can be targeted for therapeutic intervention.
Gut Microbiota and Developmental Epigenetic Regulation of Intestinal Stem Cells
We are interested in understanding how DNA methylation processes interplay with environmental cues (nutrition and microbiota) to guide the emergence and behavior of intestinal stem cells (ISCs). Using mouse models, we demonstrate that the suckling period is critical for epigenetic changes in the development of ISCs, potentially affecting intestinal health for life (Genome Biol. 2015; 16:211). We show that postnatal intestinal epigenetic regulation is significantly altered by germ-free conditions. Interestingly, the successful restoration of DNA methylation depends on the timing of microbial colonization (i.e. pre-weaning vs. after-weaning), supporting a critical window phenomenon. Currently, we are applying state-of-the-art sequencing-based techniques to achieve the ultimate genome-wide, unbiased assessment of microbial effects on ISC epigenome. We are using cutting-edge genome editing to dissect the epigenetic mechanisms that regulate ISC function in response to the gut microbiota. Our ultimate goal is to develop epigenetically targeted probiotic therapies to provide lifelong protection against intestinal disease.