The intestinal epithelium is one of the most rapidly renewing tissues in the body, and thus the ideal tissue to study somatic stem and progenitor cell biology. The small intestinal epithelium is composed of a single layer of cells that contains four major differentiated cell types as well as intestinal stem cells (ISCs) and progenitor or transit amplifying cells that replenish differentiated cells throughout life. While the past twenty years have seen great progress in our understanding of the signaling pathways and transcriptional regulators that control intestinal proliferation and differentiation, our understanding of the epigenetic factors that control these important processes is rather limited. Equally important is the identification of the intestinal stem cell niche, and the characterization of its function in molecular detail. To address this knowledge gap, I propose the following Specific Aims:
In specific Aim 1, we will determine if Foxl1+ subepithelial telocytes are required for providing critical Wnt signals during gastrointestinal development and in R-spondin free enteroid culture. We will employ our newly developed genetic and molecular tools to determine the signaling pathways controlled by telocytes during intestinal development using mouse models.
In Aim 2, we will investigate the contribution of polycomb complex mediated gene repression via histone H3K27 trimethylation on intestinal stem cell biology and regeneration. To this end, we will employ tissue and cell type specific gene ablation of two genes encoding critical H3K27me3 demethylases in the intestinal epithelium, both under homeostatic conditions and after ablation of Lgr5 stem cells.
Gastrointestinal cancer is a significant health problem, ranking fourth in incidence and second in death among cancers in the United States. Abnormal differentiation and increased proliferation of the intestinal epithelium are hallmarks of carcinogenesis. The molecular mechanisms that regulate cellular proliferation and differentiation in gastrointestinal development are far from being understood completely. Therefore, we will analyze the impact of the intestinal stem cell niche cells on intestinal growth and function, and test the contribution of histone demethylation to intestinal health.
| Shoshkes-Carmel, Michal; Wang, Yue J; Wangensteen, Kirk J et al. (2018) Subepithelial telocytes are an important source of Wnts that supports intestinal crypts. Nature 557:242-246 |
| Kieckhaefer, Julia; Lukovac, Sabina; Ye, Diana Z et al. (2016) The RNA polymerase III subunit Polr3b is required for the maintenance of small intestinal crypts in mice. Cell Mol Gastroenterol Hepatol 2:783-795 |
| Kim, Rinho; Sheaffer, Karyn L; Choi, Inchan et al. (2016) Epigenetic regulation of intestinal stem cells by Tet1-mediated DNA hydroxymethylation. Genes Dev 30:2433-2442 |
| Sheaffer, Karyn L; Elliott, Ellen N; Kaestner, Klaus H (2016) DNA Hypomethylation Contributes to Genomic Instability and Intestinal Cancer Initiation. Cancer Prev Res (Phila) 9:534-46 |
| Aoki, Reina; Shoshkes-Carmel, Michal; Gao, Nan et al. (2016) Foxl1-expressing mesenchymal cells constitute the intestinal stem cell niche. Cell Mol Gastroenterol Hepatol 2:175-188 |
| Terry, Natalie A; Lee, Randall A; Walp, Erik R et al. (2015) Dysgenesis of enteroendocrine cells in Aristaless-Related Homeobox polyalanine expansion mutations. J Pediatr Gastroenterol Nutr 60:192-9 |
| Elliott, Ellen N; Sheaffer, Karyn L; Schug, Jonathan et al. (2015) Dnmt1 is essential to maintain progenitors in the perinatal intestinal epithelium. Development 142:2163-72 |
| Elliott, Ellen N; Kaestner, Klaus H (2015) Epigenetic regulation of the intestinal epithelium. Cell Mol Life Sci 72:4139-56 |
| Jiao, Yang; Ye, Diana Z; Li, Zhaoyu et al. (2015) Protein tyrosine phosphatase of liver regeneration-1 is required for normal timing of cell cycle progression during liver regeneration. Am J Physiol Gastrointest Liver Physiol 308:G85-91 |
| Sheaffer, Karyn L; Kim, Rinho; Aoki, Reina et al. (2014) DNA methylation is required for the control of stem cell differentiation in the small intestine. Genes Dev 28:652-64 |
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