Defining the molecular mechanisms driving intestinal epithelial cell specification

肠上皮是一个动态系统，在整个生物体生命过程中不断快速地再生。这种上皮组织在隐窝和绒毛区室中，具有不同的细胞群和功能。肠隐窝含有上皮干细胞，周围是分化的Paneth细胞。这些后一种细胞表达促进生长和细胞保护肽，以确保干细胞最优地产生祖细胞。肠绒毛包含不同亚型的上皮细胞，包括肠细胞、杯状细胞和肠内分泌细胞。尽管在过去的几年中已经收集了一些关于在这种特殊情况下上皮细胞规范和维持所需的分子机制性质的线索，但所涉及的确切调控回路仍然没有很好地定义。此次发现基金的续期旨在继续***研究项目，并建议在未来五年内整合一组蛋白质之间的相互作用转录网络，其中包括我们过去几年研究过的一些蛋白质。更准确地说，我们建议的工作将集中在GATA4转录因子上，我们最近已经确定了它的特异性新的肠上皮细胞功能，随着其他相关转录调节因子的发现，它的综合转录和生物学影响。我们还打算利用我们最近在***实验室优化的创新系统模型。该生物系统由离体生长的小型上皮肠道组成，可以很好地概括肠上皮的增殖和细胞分化。本研究计划旨在确定肠上皮干细胞和分化细胞中易受肠上皮转录组调控的GATA4蛋白复合物的性质，并结合最相关的已确定的相互作用转录调控因子确定GATA4的全球肠上皮遗传靶点。我们希望这些策略将为上皮干细胞和分化细胞中上皮细胞特异性转录相互作用组的性质提供重要信息。这将使我们更好地理解对肠上皮细胞规格具有重要意义的调节因子的性质，并可能提供新的长期靶向策略，以替代产生丰富和特异性肠上皮细胞亚型的独特培养集，这些模型仍有待优化。

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 harboring 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.