The role of PHF6 in the control of hematopoietic stem cell aging.

项目总结/摘要 随着预期寿命的增加，与年龄有关的疾病已成为一个主要的健康问题。 现在认识到，干细胞衰老是系统性和器官特异性功能性衰老的驱动因素。 下降在造血系统中，干细胞老化的特征在于 具有受损的自我更新的免疫表型定义的造血干细胞（HSC） 能力和改变的分化程序，骨髓细胞群的生成增加 和淋巴潜能降低在这里，我们表明，植物同源结构域的遗传丢失 因子6（PHF 6）导致HSC连续移植能力增加，并消除了HSC的免疫抑制作用。 与年龄相关的造血衰退的发展，包括功能性造血干细胞的积累， 耗尽的HSC表现出髓样分化偏向和受损的淋巴潜能。我们 中心假设是Phf 6的缺失重构了HSC阻断的表观遗传景观， 与年龄相关的功能衰退的开始和/或进展。在这里，我们将应用 费兰多和拉巴丹实验室在造血和计算方面的专业知识 深入探讨造血表型和PHF 6失活机制 在HSC老化中的作用为了实现这一目标，我们将分析Phf 6条件性生长因子中的干细胞区室。 在人造血干细胞中CRISPR-指导的PHF 6失活后 细胞，利用体外和体内干细胞测定结合先进的 应用于单细胞转录组学和表观基因组学的计算分析工具。这些 研究将最终促进新的靶向治疗的发展， 来自老年供体的造血干细胞的植入能力和用于治疗 与年龄相关的HSC恶化导致的病理学。

Project Summary/Abstract As life expectancy increases age-associated pathologies have become a major health problem. It is now recognized that stem cell aging is a driver of systemic and organ-specific functional decline. In the hematopoietic system stem cell aging is characterized by accumulation of immunophenotypically-defined hematopoietic stem cells (HSCs) with impaired self-renewal capacity and altered differentiation programs with increased generation of myeloid populations and decreased lymphoid potential. Here we show that genetic loss of Plant Homeodomain Factor 6 (PHF6) results in increased HSC serial transplantation capacity and abrogates the development of age-associated hematopoietic decay including the accumulation of functionally exhausted HSCs displaying myeloid differentiation bias and impaired lymphoid potential. Our central hypothesis is that loss of Phf6 reconfigures the epigenetic landscape of HSCs blocking the initiation and/or progression of age-associated functional decline. Here we will apply the combined expertise of the Ferrando and Rabadan labs in hematopoiesis and computational biology to explore in depth the hematopoietic phenotypes and mechanisms of PHF6 inactivation in HSC aging. Towards this goal we will analyze the stem cell compartment in Phf6 conditional knockout mice and after CRISPR-directed PHF6 inactivation in human hematopoietic stem cells, leveraging in vitro and in vivo stem cell assays in combination with advanced computational analytical tools applied to single cell transcriptomics and epigenomics. These studies will ultimately facilitate the development of new targeted therapies aimed at improving the engraftment capacity of hematopoietic stem cells from aged donors and for the treatment of pathologies resulting from age-associated HSC deterioration.