Transcriptional regulation of esophageal stem cell gene signature

食管干细胞基因特征的转录调控

• 批准号: RGPIN-2019-06185
• 负责人: Giroux, Véronique
• 金额: $ 2.19万
• 依托单位: Université de Sherbrooke
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=743416
• 关键词: Transcriptional; regulation; esophageal; stem; cell

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.

组织的维持是由罕见的细胞保证的，这些细胞是长寿的，可以自我更新，并产生组织的所有细胞类型，称为干细胞。干细胞确保在正常条件下产生新细胞，以补偿由于细胞死亡或终末分化以及组织再生过程中的细胞损失。干细胞在皮肤和消化道等高周转组织中特别重要。食管由称为复层鳞状上皮的多层上皮内衬，其形成保护组织免受食管腔中可发现的严峻环境的紧密屏障。在我们的研究之前，食管上皮中干细胞的存在仍然存在争议。我们最近发现并鉴定了第一批小鼠食管干细胞。这些细胞由角蛋白15（Krt 15）标记，并显示出与干细胞群一致的特征，如自我更新和再生能力。Krt 15+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理解。尽管如此，我们仍然了解很少的转录调控，驱动细胞命运的决定和干细胞的维持在食管上皮。该项目的长期目标是确定参与食管干细胞维持的转录网络的性质。我们已经确定了Krt 15+食管干细胞的转录谱，并观察到与Krt 15-细胞相比，Krt 15+细胞中Ascl 2基因转录物的大量上调。ASCL 2是与其他组织中的自我更新和细胞增殖相关的转录因子。因此，短期目标是研究转录因子ASCL 2作为食管干细胞基因签名和食管上皮稳态转录调控的潜在候选者的影响。我们将通过两个具体的目标来实现这一目标：1）分析Ascl 2缺失对食管上皮细胞自我更新的影响。2)确定食管上皮细胞中的ASCL 2结合伴侣和基因靶点。 我们将使用几种3D细胞培养模型结合转录组学和RNomics方法来实现这些目标。总之，通过剖析ASCL 2对食管细胞自我更新的作用以及ASCL 2这种作用的转录机制，我们独特的研究计划将提高我们对食管干细胞生物学的认识。