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 theorganism life. This epithelium is organized in crypt and villus compartments harboring distinct cellpopulations and functions. Intestinal crypts contain epithelial stem cells surrounded by differentiatedPaneth cells. These latter cells express growth-promoting and cell-protective peptides to ensureoptimal production of progenitors from the stem cells. Intestinal villi contain differentiated subtypesof epithelial cells including enterocytes, goblet and enteroendocrine cells. Although some clues havebeen collected over the past years on the nature of the molecular mechanisms that are required forepithelial cell specification and maintenance in this particular context, the exact regulatory circuitinvolved is still not well defined. This renewal of Discovery Grant intends to pursue this program ofresearch and proposes to integrate, over the next five years, the interactive transcriptional networkbetween a set of proteins including some of which we have studied over the past years. Moreprecisely, our proposed work will focus on the GATA4 transcription factor, for which we haverecently identified specific novel intestinal epithelial cell functions, toward its integratedtranscriptional 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 inthe laboratory. This biological system consists of mini epithelial guts growing ex vivo that perfectlyrecapitulate proliferation and cytodifferentiation of the intestinal epithelium. This research programwill aim to define the nature of GATA4 protein complexes susceptible to regulate the intestinalepithelial transcriptome in stem and differentiated cells and to define the global intestinal epithelialgenetic targets of GATA4 in combination to most relevant identified interacting transcriptionregulator(s). It is our hope that these strategies will provide crucial information on the nature of theepithelial 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 cellspecification and perhaps provide novel long-term targeting strategies to alternatively produceunique culture sets of enriched and specific subtypes of intestinal epithelial cells, models that stillawait to be optimized.