Defining the molecular mechanisms driving intestinal epithelial cell specification

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The intestinal epithelium is a dynamic system that constantly and rapidly regenerates throughout the organism life. This epithelium is organized in crypt and villus compartments harbouring distinct cell populations and functions. Intestinal crypts contain epithelial stem cells surrounded by differentiated Paneth cells. These latter cells express growth-promoting and cell-protective peptides to ensure optimal production of progenitors from the stem cells. Intestinal villi contain differentiated subtypes of epithelial cells including enterocytes, goblet and enteroendocrine cells. Although some clues have been collected over the past years on the nature of the molecular mechanisms that are required for epithelial cell specification and maintenance in this particular context, the exact regulatory circuit involved is still not well defined. This renewal of Discovery Grant intends to pursue this program of research and proposes to integrate, over the next five years, the interactive transcriptional network between a set of proteins including some of which we have studied over the past years. More precisely, our proposed work will focus on the GATA4 transcription factor, for which we have recently identified specific novel intestinal epithelial cell functions, toward its integrated transcriptional and biological impact with the discovery of other relevant transcriptional regulators. We also intend to take advantage of an innovative system model that we have recently optimized in the laboratory. This biological system consists of mini epithelial guts growing ex vivo that perfectly recapitulate proliferation and cytodifferentiation of the intestinal epithelium. This research program will aim to define the nature of GATA4 protein complexes susceptible to regulate the intestinal epithelial transcriptome in stem and differentiated cells and to define the global intestinal epithelial genetic targets of GATA4 in combination to most relevant identified interacting transcription regulator(s). It is our hope that these strategies will provide crucial information on the nature of the epithelial cell specific transcriptional interactome(s) in both epithelial stem and differentiated cells. This will allow a better understanding of the nature of regulators important for intestinal epithelial cell specification and perhaps provide novel long-term targeting strategies to alternatively produce unique culture sets of enriched and specific subtypes of intestinal epithelial cells, models that still await to be optimized.