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

组蛋白 4 表观遗传景观对造血干细胞衰老的调节

• 批准号: 387876811
• 负责人: Professor Dr. Hartmut Geiger
• 金额: --
• 依托单位: Institut für Molekulare Medizin
• 依托单位国家: 德国
• 项目类别: Research Units
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/387876811?language=en
• 关键词: Regulation; histone; epigenetic; landscape; upon

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.

随着年龄的增长，急性髓性白血病（AML）的发病率明显增加。因此，AML是一种与衰老有关的疾病。此外，老年人（70岁以上）的AML的性质通常与年轻患者的AML不同。人们提出了多种理论来解释AML随着年龄增长而增加的发病率和性质的变化。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，随着年龄的增长，遗传和/或表观遗传稳定性降低。虽然随着年龄的增长，基因突变有一个小而显著的增加，但随着年龄的增长，表观遗传格局的变化在过去几年中才刚刚开始被揭示出来。据推测，表观基因组的改变导致造血干细胞和白血病干细胞自我更新和分化的变化。表观遗传标记可以进行药理学修饰，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，对于哪些基因和机制调节了hsc在衰老过程中表观遗传组成的变化，我们知之甚少。识别这些参与者可能成为设计合理方法来影响hsc表观遗传特征中与衰老相关的变化的先决条件，并针对与衰老相关的白血病（如AML）中的这些变化。该项目旨在鉴定H4K16ac修饰因子在衰老hsc中发生的变化，并将测试它们对白血病发生和进展的作用。我们将采用比较测序方法以及基于小鼠重组近缘（RI）株hsc的遗传方法，最终揭示导致hsc中组蛋白4表观遗传景观随年龄变化的驱动遗传事件，并将确定它们对AML发生/进展的贡献程度。