Regulation of the histone 4 epigenetic landscape upon hematopoietic stem cell aging

急性髓细胞白血病（AML）的发病率随着年龄的增长而显著增加。因此，AML是一种与衰老相关的疾病。此外，老年人（70岁以上）AML的性质通常与年轻患者中发现的AML不同。已经提出了多种理论来解释AML在衰老时的发病率增加和性质变化。一个突出的理论是与AML相关的潜在干细胞，造血干细胞（HSC）老化，并且随着老化，遗传和/或表观遗传稳定性降低。虽然随着年龄的增长，基因突变会有一个小的但显著的增加，但在过去的几年里，随着年龄的增长，表观遗传景观的变化才刚刚开始被揭开。假设表观基因组的改变是HSC和白血病干细胞自我更新和分化变化的原因。表观遗传标记可以被修饰，这使得它们成为影响衰老相关白血病的潜在靶点。不幸的是，很少有人知道是什么基因和机制调节的变化，在造血干细胞的表观遗传组成老化。识别这些参与者可能成为设计合理方法的先决条件，以影响HSC表观遗传特征中与衰老相关的变化，并靶向与衰老相关的白血病（如AML）中的这些变化。该项目旨在鉴定在老化HSC中改变的H4 K16 ac景观的修饰剂，并将测试它们对白血病起始和进展的作用。我们将采用比较测序方法以及基于来自小鼠重组近交系（RI）株的HSC的遗传方法，以最终解开导致衰老时HSC中组蛋白4表观遗传景观变化的驱动遗传事件，并将确定它们对AML启动/进展的贡献程度。

There is a marked increase in the incidence of acute myelogenous leukemia (AML) with age. AML is thus an aging-related disease. Also, the nature of the AML in the elderly (70+) is usually distinct from AML found in younger patients. Multiple theories have been put forward to explain both the increased incidence and the change in nature of AML upon aging. One prominent theory is that the underlying stem cell associated with AML, the hematopoietic stem cell (HSC) ages, and with aging there is reduced genetic and/or epigenetic stability. While there is a small, but significant increase in genetic mutations upon aging, changes in the epigenetic landscape upon aging have just begun to be unraveled over the last couple of years. It is assumed that alterations in the epigenome are causative for changes in self-renewal and differentiation of HSCs and leukemic stem cells. Epigenetic marks can be pharmacologically modified, which render them potential targets to influence aging-related leukemia. Unfortunately, little is known about what genes and mechanisms regulate of changes in the epigenetic make-up of HSCs upon aging. Identification of these players might become a pre-requisite to design rational approaches to influence aging-related changes in the epigenetic signature of HSCs, and to target these changes in aging-related leukemia like AML. This projects aims at the identification at modifiers of the H4K16ac landscape that is changed in aged HSCs and will test their action on leukemia initiation and progression. We will employ comparative sequencing approaches as well as a genetic approach based on HSCs from murine recombinant inbred (RI) strains to ultimately unravel driver genetic events that contribute to changes in the epigenetic landscape of Histone 4 in HSCs upon aging, and will determine the extent to which they contribute to AML initiation/progression.