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SWI/SNF Chromatin Remodeling in Multipotency

多能性 SWI/SNF 染色质重塑

基本信息

批准号：
1557891
负责人：
Laura Mathies
金额：
$ 69万
依托单位：
Virginia Commonwealth University
依托单位国家：
美国
项目类别：
Continuing Grant
财政年份：
2016
资助国家：
美国
起止时间：
2016-03-15 至 2023-02-28
项目状态：
已结题

来源：
https://www.nsf.gov/awardsearch/showAward?AWD_ID=1557891&HistoricalAwards=false
关键词：
SWI SNF Chromatin Remodeling Multipotency

项目摘要

Stem cells have the potential to generate a variety of different cell types and are important for the renewal of cells in adulthood, while differentiated cells are committed to perform a specific function. In recent years, researchers have found that differentiated cells can be converted into stem cells by introducing a few key genetic factors into the differentiated cell. In order to harness this potential for regenerative medicine, it is important to understand the genetic factors that give stem cells their unique potential. The genetic model organism Caenorhabditis elegans has many advantages for studying this process. Importantly, the fates of all cells in the animal are known. This research focuses on two cells that arise through a single cell division and have very different potential: one is capable of making all support cells of the reproductive system, while the other is differentiated. The genetic factors that are different between these two cells will be identified and this will provide insight into what makes a stem cell different from a differentiated cell. In order to train the next generation of STEM professionals, this research will be incorporated into an advanced undergraduate laboratory that gives students a genuine research experience. Students are expected to be from diverse backgrounds, including racial and ethnic groups that are traditionally underrepresented in STEM fields.Adult stem and progenitor cells are capable of producing a few related cell types. The genes and molecular mechanisms that regulate and determine this capacity are not well understood. This proposal uses progenitors of the C. elegans reproductive system as a model for defining the genetic determinants of multipotency. The somatic gonadal progenitors (SGPs) are multipotent progenitors that generate all somatic tissues of the reproductive system. Each SGP is the product of a cell division that produces one SGP and one differentiated cell, the head mesodermal cell (hmc). Therefore, in this single cell division the potential to generate all of the somatic gonadal types is differentially segregated into one daughter cell. SWI/SNF chromatin remodeling complexes are highly conserved, large protein complexes that regulate chromatin structure and result in gene activation or repression. Molecularly distinct SWI/SNF complexes are expressed in pluripotent stem cells, multipotent progenitors, and differentiated cells, suggesting that different SWI/SNF complexes are likely to play important roles in each of these different cell states. Components of the C. elegans SWI/SNF complex are required to distinguish SGPs from their differentiated hmc sisters. The goals of this proposal are to identify the genes that distinguish multipotent SGPs from their differentiated hmc sisters, and to identify the mechanisms by which SWI/SNF chromatin remodeling complexes regulate these cell fates. These experiments will provide insight into the genes and molecular mechanisms that distinguish multipotent progenitors from differentiated cells, and will identify the role SWI/SNF chromatin remodeling complexes in these cell fates.

干细胞具有产生各种不同细胞类型的潜力，并且对于成年期细胞的更新非常重要，而分化的细胞致力于执行特定功能。近年来，研究人员发现，通过向分化细胞中引入一些关键的遗传因子，可以将分化细胞转化为干细胞。为了利用再生医学的这种潜力，重要的是要了解赋予干细胞独特潜力的遗传因素。遗传模式生物秀丽隐杆线虫具有许多研究这一过程的优势。重要的是，动物体内所有细胞的命运都是已知的。这项研究的重点是两种细胞，它们通过单细胞分裂产生，具有非常不同的潜力：一种能够制造生殖系统的所有支持细胞，而另一种是分化的。这两种细胞之间不同的遗传因素将被识别，这将提供深入了解是什么使干细胞不同于分化细胞。为了培养下一代STEM专业人员，这项研究将被纳入一个先进的本科实验室，为学生提供真正的研究体验。预计学生将来自不同的背景，包括传统上在STEM领域代表性不足的种族和民族。成人干细胞和祖细胞能够产生一些相关的细胞类型。调节和决定这种能力的基因和分子机制还不清楚。该建议使用C. elegans生殖系统作为一个模型来定义多能性的遗传决定因素。体细胞性腺祖细胞（SGPs）是产生生殖系统所有体细胞组织的多能祖细胞。每个SGP都是细胞分裂的产物，细胞分裂产生一个SGP和一个分化的细胞，即头部中胚层细胞（hmc）。因此，在这种单细胞分裂中，产生所有体细胞性腺类型的潜力被差异地分离到一个子细胞中。SWI/SNF染色质重塑复合物是高度保守的大蛋白复合物，其调节染色质结构并导致基因活化或抑制。分子上不同的SWI/SNF复合物在多能干细胞、多能祖细胞和分化细胞中表达，表明不同的SWI/SNF复合物可能在这些不同的细胞状态中的每一种中发挥重要作用。C.需要elegans SWI/SNF复合体来区分SGP与其分化的hmc姐妹篇。该提案的目标是确定区分多能SGPs与其分化的hmc姐妹篇的基因，并确定SWI/SNF染色质重塑复合物调节这些细胞命运的机制。这些实验将深入了解区分多能祖细胞和分化细胞的基因和分子机制，并将确定SWI/SNF染色质重塑复合物在这些细胞命运中的作用。