Aging Human Hematopoietic Stem Cells Manifest Profound Epigenetic Reprogramming of Enhancers That May Predispose to Leukemia (H3 ChIPseq)

Aging is associated with functional decline of hematopoietic stem cells (HSC) as well as an increased risk of myeloid malignancies. We performed an integrative characterization of epigenomic and transcriptomic changes, including single-cell RNA-seq, during normal human aging. Lineage-CD34+CD38- cells (HSC-enriched, HSCe) undergo age-associated epigenetic reprogramming consisting of redistribution of DNA methylation and reductions in H3K27ac, H3K4me1 and H3K4me3. This reprogramming of aged HSCe globally targets developmental and cancer pathways which are comparably altered in AML of all ages; encompassing loss of 4,656 active enhancers, 3,091 bivalent promoters, and deregulation of several epigenetic modifiers and key hematopoietic transcription factors, such as KLF6, BCL6 and RUNX3. Notably, in vitro downregulation of KLF6 results in impaired differentiation, increased colony forming potential and changes in expression that recapitulate aging and leukemia signatures. Thus, age-associated epigenetic reprogramming may form a predisposing condition for the development of age-related AML.

衰老与造血干细胞（hematopoietic stem cells, HSC）功能衰退以及髓系恶性肿瘤风险升高密切相关。本研究对正常人类衰老过程中的表观基因组与转录组变化进行了整合表征，其中包含单细胞RNA测序（single-cell RNA-seq）。谱系阴性CD34阳性CD38阴性细胞（富集造血干细胞的细胞群，HSCe）会发生衰老相关的表观遗传重编程，具体表现为DNA甲基化分布重塑，以及组蛋白H3赖氨酸27乙酰化（H3K27ac）、组蛋白H3赖氨酸4单甲基化（H3K4me1）与组蛋白H3赖氨酸4三甲基化（H3K4me3）水平降低。衰老HSCe的这种重编程在全局层面靶向发育与癌症通路，这类通路在各年龄段的急性髓系白血病（acute myeloid leukemia, AML）中均存在类似改变；该重编程涉及4656个活性增强子、3091个二价启动子的丢失，以及多种表观遗传修饰因子与关键造血转录因子（如KLF6、BCL6及RUNX3）的表达失调。值得注意的是，体外下调KLF6会导致细胞分化受损、集落形成能力增强，并引发重现衰老与白血病特征的表达谱改变。综上，衰老相关的表观遗传重编程可能构成年龄相关性急性髓系白血病发生的易感基础。