Transcriptional regulation of skin stem cells and their niche

皮肤干细胞及其生态位的转录调控

• 批准号: 10252398
• 负责人: Rui Yi
• 金额: $ 20.37万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-28 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10252398
• 关键词: ATAC-seq; Adult; Affect; Biology; Cell Adhesion; Cell Compartmentation; Cell Maintenance; Cell division; Cell physiology; Cells; Chromatin; DNA Sequence Alteration; DNA biosynthesis; Enhancers; FOXC1 gene; Gene Expression; Generations; Genes; Genomics; Goals; Hair; Hair follicle structure; Homeostasis; Individual; Knock-out; Knockout Mice; Knowledge; Lead; Life; Maintenance; Mediating; Modeling; Molecular; Mus; Natural regeneration; Organism; Phase; Play; Property; Regenerative Medicine; Regulation; Research; Research Personnel; Role; Signal Transduction; Skin; System; Time; Tissues; Transcriptional Regulation; adult stem cell; cell motility; genomic tools; in vivo; innovation; insight; migration; mouse model; response; self-renewal; stem cell biology; stem cell division; stem cell population; stem cells; tissue regeneration; transcription factor; transcriptome; tumorigenesis; wound healing

Project Summary: The overarching goal of the proposed research is to understand how skin stem cells maintain their identity when responding to cell intrinsic and extrinsic signals for self-renewal or differentiation. Self-renewal of stem cells is achieved by either symmetrical or asymmetrical cell division, through which new generations of stem cells are produced to replenish the stem cell population. However, DNA replication and cell division of adult stem cells can also lead to generation and accumulation of DNA mutations that compromise stem cell function and, in some cases, tumorigenesis. In the skin, hair follicle stem cells acquire quiescence to minimize cell turnover and division. However, it remains poorly understood how these stem cells transition between self-renewing and quiescent phases and the requirement of quiescence for long-term maintenance of stem cells. These questions have challenged investigators, because these self-renewing and quiescent stem cells are rare and usually heterogeneous in most adult tissues, making their isolation and characterization difficulty. In the skin of early adult mice, hair follicle stem cells are highly synchronized for self-renewal and quiescence. This property makes hair follicle stem cells an ideal system to investigate this fundamental question in stem cell biology. Recently, we have identified a transcription factor, Foxc1, induced in self-renewing but not quiescent hair follicle stem cells and their niche to reinforce quiescence. This finding uncovers an adaptive response of quiescent stem cells to stem cell activation during self- renewal and illuminates a path to further investigate mechanisms that control cellular state transitions in adult stem cells. In this proposal, we will utilize our innovative genomic tools and mouse models to understand adaptive control of stem cell quiescence and self-renewal mediated by transcription factors. We will first determine how multiple transcription factors regulate stem cell quiescence by coordinating transcriptional control of common and unique targets. We will determine the requirement of quiescence for long-term maintenance of hair follicle stem cells (Aim 1). We will then investigate the differences in open chromatin between self-renewing and quiescent stem cells. We will examine how the BMP signaling is controlled by transcription factors (Aim 2). Finally, we will investigate the mechanism of club hair anchorage mediated by transcription factors (Aim 3). The knowledge gained from these studies will enhance our understanding of quiescence control in hair follicle stem cells.

项目总结： 这项拟议研究的首要目标是了解皮肤干细胞是如何维持的 它们在响应细胞内部和外部信号进行自我更新时的身份 差异化。干细胞的自我更新是通过对称或非对称细胞实现的。 分裂，通过分裂产生新一代的干细胞来补充干细胞 人口。然而，成体干细胞的DNA复制和细胞分裂也可能导致 DNA突变的产生和积累会损害干细胞功能，并在 某些情况下，肿瘤的发生。在皮肤中，毛囊干细胞获得静止以最小化 细胞周转和分裂。然而，人们仍然很少了解这些干细胞如何 自更新与静止状态的转换及对静止状态的要求 干细胞的长期维持。这些问题向调查人员提出了挑战，因为 这些自我更新和静止的干细胞是罕见的，在大多数成年人中通常是异种的。 组织，使它们的分离和鉴定变得困难。在早期成年小鼠的皮肤上，毛发 卵泡干细胞高度同步化，可以自我更新和静止。此属性使 毛囊干细胞是研究干细胞这一基本问题的理想系统 生物学。最近，我们已经鉴定出一种转录因子Foxc1，它可以诱导自我更新，但 不静止的毛囊干细胞及其利基加强静止。这一发现 揭示静止干细胞在自我修复过程中对干细胞激活的适应性反应 更新并照亮了进一步研究控制细胞状态的机制的途径 成体干细胞的转变。在这项提案中，我们将利用我们的创新基因组工具和 小鼠模型理解干细胞静止和自我更新的适应性控制 由转录因子介导。我们将首先确定多个转录因子如何 通过协调常见和独特的转录调控来调节干细胞的静止 目标。我们将确定长期维护头发所需的静止条件 卵泡干细胞(目标1)。然后我们将研究开放染色质的差异 自我更新和静止的干细胞。我们将研究BMP信号是如何由 转录因子(目标2)。最后，我们将对杆状头发锚定的机理进行探讨 由转录因子介导(目标3)。从这些研究中获得的知识将 提高对毛囊干细胞静息调控的认识。