Alterations of H3K9me2 in hematopoietic stem cells: implications for aging and myeloid leukemogenesis

造血干细胞中 H3K9me2 的改变：对衰老和骨髓性白血病发生的影响

• 批准号: 387875922
• 负责人: Professor Dr. Hartmut Geiger, since 11/2018
• 金额: --
• 依托单位: Institut für Molekulare Medizin
• 依托单位国家: 德国
• 项目类别: Research Units
• 财政年份: 2017
• 资助国家: 德国
• 起止时间: 2016-12-31 至 2020-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/387875922?language=en
• 关键词: Alterations; H3K9me2; hematopoietic; stem; cells

Upon aging HSCs show a critical functional decline that is paralleled by changes in global and local DNA and histone methylation as well as histone acetylation. This epigenetic drift might contribute to aberrant DNA transcription or impair DNA replication and repair, and might by this means contribute to the development of cancer. For instance, AML is predominantly a disease of older patients that originates in hematopoietic progenitor/stem cells and affects substantially the epigenome. The epigenome of leukemia stem cells (LSCs) is maintained in the myeloblast and influence aggressiveness and outcome of the disease. Recently it was shown that the histone demethylase JMJD1C functions as a coactivator for RUNX1RUNX1T1 (formerly AML1ETO) and is required for its transcriptional program in AML by maintaining low levels specifically of H3K9me2, further implying a direct connection between changes in epigenetics of HSCs and AML. H3K9me2 though has not been studied so far in HSCs and upon aging and leukemic transformation. Preliminary data from my laboratory indicate that the distribution of H3K9me2 in the nucleus of quiescent murine HSCs and in daughter cells upon murine HSC division is distinctly altered upon aging. Treatment of aged HSCs with CASIN restored a youthful distribution of H3K9me2 in aged HSCs and in daughter cells upon stem cell division.Based on my preliminary data and on data recently published by others, I hypothesize that alterations in H3K9me2 deposition upon aging of HSCs contribute to the aging-associated transition of HSCs to AML stem cells and targeting H3K9me2 distribution via CASIN treatment and/or H3K9me2 levels via inhibition of the histone demethylase JMJD1C could represent an approach to decrease aggressiveness of LSCs in AML.Therefore the current proposal aims are (1) to determine the extent of the alterations in H3K9me2 distribution/levels upon aging of murine HSCs and investigate whether the aging-associated changes are reverted to a youthful level by CASIN treatment of by inhibition of JMJD1C activity; (2) to investigate whether human HSCs present, similar to murine HSCs, with changes in H3K9me2 distribution upon aging; (3) to determine whether AML stem cells present with altered H3K9me2 distribution and investigate whether targeting the level and/or the distribution of H3K9me2 in murine LSCs alters leukemia initiation and progression.

衰老后，HSC 表现出严重的功能衰退，同时伴随着整体和局部 DNA 以及组蛋白甲基化和组蛋白乙酰化的变化。这种表观遗传漂移可能导致 DNA 转录异常或损害 DNA 复制和修复，并可能通过这种方式促进癌症的发展。例如，AML主要是老年患者的一种疾病，起源于造血祖细胞/干细胞并显着影响表观基因组。白血病干细胞 (LSC) 的表观基因组保留在成髓细胞中，并影响疾病的侵袭性和结果。最近的研究表明，组蛋白去甲基化酶 JMJD1C 作为 RUNX1RUNX1T1（以前称为 AML1ETO）的共激活剂发挥作用，并且是其在 AML 中通过维持低水平的 H3K9me2 转录程序所必需的，进一步暗示 HSC 的表观遗传学变化与 AML 之间存在直接联系。但迄今为止，H3K9me2 尚未在 HSC 中以及衰老和白血病转化中进行研究。我实验室的初步数据表明，H3K9me2 在静止鼠 HSC 细胞核中以及鼠 HSC 分裂时的子细胞中的分布随着年龄的增长而明显改变。用 CASIN 治疗衰老的 HSC，恢复了衰老 HSC 和干细胞分裂后子细胞中 H3K9me2 的年轻分布。根据我的初步数据和其他人最近发表的数据，我假设 HSC 衰老时 H3K9me2 沉积的变化有助于衰老相关的 HSC 向 AML 干细胞的转变，并通过 CASIN 治疗靶向 H3K9me2 分布和/或通过抑制组蛋白靶向 H3K9me2 水平去甲基酶 JMJD1C 可以代表一种降低 AML 中 LSC 侵袭性的方法。因此，当前提案的目标是 (1) 确定小鼠 HSC 衰老时 H3K9me2 分布/水平的变化程度，并研究与衰老相关的变化是否得到恢复通过CASIN治疗通过抑制JMJD1C活性达到年轻水平； (2) 研究人类 HSC 是否与小鼠 HSC 类似，随着衰老而出现 H3K9me2 分布的变化； (3) 确定 AML 干细胞是否存在 H3K9me2 分布改变，并研究针对小鼠 LSC 中 H3K9me2 的水平和/或分布是否会改变白血病的发生和进展。