- Associate Professor
- Baylor College of Medicine
- Houston, TX, US
- Advanced Training from M.D. Anderson Cancer Center
- Advanced Training from Johns Hopkins Hospital
- Ph.D. from Shanghai Second Medical College
- MD from Zhenjiang Medical School
- Epigenetics, Development and Human Disease
My laboratory is interested in the epigenetic mechanisms in health and disease with a focus on transcriptional regulation by DNA methylation across development and during tumorigenesis. We use a combination of genomics, epigenomics, and next-generation gene editing approaches and a variety of model systems including cell culture, ex vivo organoids, germ-free and gnotobiotic mice.
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.
- Yu DH, Gadkari M, Zhou Q, Yu S, Gao N, Guan Y, Schady D, Roshan TN, Chen MH, Laritsky E, Ge Z, Wang H, Chen R, Westwater C, Bry L, Waterland RA, Moriarty C, Hwang C, Swennes AG, Moore SR, Shen L.. "Postnatal epigenetic regulation of intestinal stem cells requires DNA methylation and is guided by the microbiome.." Genome Biol.. 2015 September 30;16:211. Pubmed PMID: 26420038
- Yu DH, Waterland RA, Zhang P, Schady D, Chen MH, Guan Y, Gadkari M, Shen L.. "Targeted p16Ink4a epimutation causes tumorigenesis and reduces survival in mice.." J Clin Invest.. 2014;124(9):3708-12. Pubmed PMID: 25061879
- Yu DH, Ware C, Waterland RA, Zhang J, Chen MH, Gadkari M, Kunde-Ramamoorthy G, Nosavanh LM, Shen L. "Developmentally programmed 3' CpG island methylation confers tissue- and cell-type-specific transcriptional activation.." Mol. Cell. Biol.. 2013 May;33(9):1845-58. Pubmed PMID: 23459939
- Shen L, Kantarjian H, Guo Y, Lin E, Shan J, Huang X, Berry D, Ahmed S, Zhu W, Pierce S, Kondo Y, Oki Y, Jelinek J, Saba H, Estey E, Issa JP. "DNA methylation predicts survival and response to therapy in patients with myelodysplastic syndromes.." J. Clin. Oncol.. 2010 February 1;28(4):605-13. Pubmed PMID: 20038729
- Shen L, Kondo Y, Guo Y, Zhang J, Zhang L, Ahmed S, Shu J, Chen X, Waterland RA, Issa JP. "Genome-wide profiling of DNA methylation reveals a class of normally methylated CpG island promoters.." PLoS Genet.. 2007 October;3(10):2023-36. Pubmed PMID: 17967063