Transcriptional regulation of esophageal stem cell gene signature

组织的维持是由稀有细胞保证的，这些细胞寿命长，可以自我更新，并产生组织的所有细胞类型，即干细胞。干细胞在正常情况下保证新细胞的产生，以补偿因细胞死亡或终末分化而导致的细胞损失，并在组织再生过程中发挥作用。干细胞在高周转率的组织中尤其重要，如皮肤和消化道。食管由多层上皮构成，称为层状鳞状上皮，它形成了一个紧密的屏障，保护组织免受食管腔内恶劣环境的影响。在我们的研究之前，干细胞在食管上皮中的存在一直存在争议。我们最近鉴定并鉴定了第一批小鼠食管干细胞。这些细胞由角蛋白15 （Krt15）标记，并显示出与干细胞群体一致的特征，如自我更新和再生能力。Krt15+食管干细胞的鉴定和描述极大地改变了我们对食管上皮生物学的认识。尽管如此，我们仍然对食管上皮中驱动细胞命运决定和干细胞维持的转录调控知之甚少。

Tissue maintenance is assured by rare cells that are long-lived, can self-renew and give rise to all cell types of a tissue, known as stem cells. Stem cells assure the production of new cells in normal condition to compensate for cell loss due to cell death or terminal differentiation, and also during tissue regeneration. Stem cells are particularly important in tissues with high turnover such as the skin and the digestive tract. The esophagus is lined by a multilayered epithelium called stratified squamous epithelium which forms a tight barrier protecting the tissue from the austere environment that can be found in the esophageal lumen. The existence of stem cells in the esophageal epithelium remained controversial until our study. We recently identified and characterized the first population of mouse esophageal stem cells. These cells are marked by Keratin 15 (Krt15) and display characteristics consistent with a stem cell population such as self-renewal and regenerative capacity. The identification and description of Krt15+ esophageal stem cells have dramatically changed our understanding of esophageal epithelial biology. Nonetheless, we still understand little about the transcriptional regulation that drives cell fate decision and stem cell maintenance in the esophageal epithelium. The long-term goal of this project is to determine the nature of the transcriptional network involved in the maintenance of esophageal stem cells. We have determined the transcriptional profile of Krt15+ esophageal stem cells and observed a massive upregulation of Ascl2 gene transcript in Krt15+ cells when compared to Krt15- cells. ASCL2 is a transcription factor associated with self-renewal and cell proliferation in other tissues. Therefore, the short-term objective is to investigate the impact of transcriptional factor ASCL2 as a potential candidate for transcriptional regulation of the esophageal stem cell gene signature and esophageal epithelial homeostasis. We will pursue this objective through two specific aims: 1) Analyze the impact of Ascl2 loss on self-renewal of esophageal epithelial cells. 2) Determine ASCL2 binding partners and gene targets in esophageal epithelial cells. We will use several 3D cell culture models in combination with transcriptomics and RNomics approaches to accomplish these aims. Altogether, by dissecting the role of ASCL2 on esophageal cell self-renewal and the transcriptional mechanisms underlying this role of ASCL2, our unique research program will improve our knowledge on esophageal stem cell biology.