Remodeling the epithelial stem cell

描述(申请人提供)：我们最近已经证明染色质重构体Mi-2b对于造血干细胞(HSC)的自我更新特性以及允许其后代沿着造血系统的不同谱系分化的可塑性至关重要。我们现在建议将这一分析扩展到毛囊干细胞，其独特的特性允许对这些细胞及其衍生物中的基因功能进行严格的分析。我们的初步数据显示，Mi-2b对于成人毛囊的维持是必要的。我们现在将利用现有的方法在两个不同的卵泡干细胞群体中特异性地删除Mi-2b，这两个群体是长寿命的卵泡隆起干细胞和短寿命的基质干细胞。这一方法将被实验室新开发的技术扩大，以靶向和纯化这些不同的干细胞类型。我们将描述在这些群体中删除Mi-2b的影响以及受影响的分子途径。通过将这些结果与已经在造血系统中获得的结果进行比较，我们将深入了解控制成人躯体干细胞行为的常见遗传级联。重组染色质以调节基因可及性的酶在成人干细胞中发挥着关键作用，既可以平衡某些基因的潜在表达，也可以主动抑制其他基因的表达。我们之前已经证明了染色质重构体Mi-2b在造血干细胞的维持及其后代分化中的作用，并鉴定了这些细胞中调控的基因。我们建议在另一个成人干细胞群体中描述对Mi-2b的需求，即成人毛囊的角质形成细胞干细胞。通过比较Mi-2b在这两种不同干细胞中的功能，我们希望确定对干细胞行为至关重要的共同功能，同时确定这些不同类型干细胞特有的活动。

DESCRIPTION (provided by applicant): We have recently shown that the chromatin remodeler Mi-2b is critical for the self-renewal properties of the hematopoietic stem cell (HSC) and for the plasticity that allows its progeny to differentiate along the various lineages of the hematopoietic system. We now propose to extend this analysis to the stem cells of the hair follicle whose unique properties allow rigorous analysis of gene function in these cells and their derivatives. Our preliminary data show that Mi-2b is necessary for maintenance of the hair follicle in the adult. We will now exploit existing methods to delete Mi-2b specifically in two distinct follicular stem cell populations, the long-lived follicular bulge stem cell and the short-lived matrix stem cell. This approach will be augmented by techniques newly developed in the laboratory to target and purify these distinct stem cell types. We will characterize the effects of deleting Mi-2b in these populations and the molecular pathways affected. By comparing these with results already obtained in the hematopoietic system, we will gain insight into the common genetic cascades that control adult somatic stem cell behavior. Enzymes that remodel chromatin to regulate the accessibility of genes play a critical role in adult stem cells both by poising some genes for potential expression and by actively repressing the expression of others. We have previously demonstrated the role of the chromatin remodeler Mi-2b in the maintenance of the hematopoietic stem cell and differentiation of its progeny and identified the genes regulated in these cells. We propose to characterize the requirement for Mi-2b in another adult stem cell population, the keratinocyte stem cells of the adult hair follicle. By comparing the function of Mi-2b in these two different stem cells, we hope to identify common functions that are fundamental to stem cell behavior while identifying activities that are specific to these different types of stem cells.