Aging Human Hematopoietic Stem Cells Manifest Profound Epigenetic Reprogramming of Enhancers That May Predispose to Leukemia (RNA-Seq of LMNA KD)

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（包括单细胞RNA测序（single-cell RNA-seq））进行了整合表征。谱系阴性CD34阳性CD38阴性细胞（造血干细胞富集群，HSC-enriched, HSCe）会发生衰老相关的表观遗传重编程，表现为DNA甲基化重分布以及H3K27乙酰化（H3K27ac）、H3K4单甲基化（H3K4me1）与H3K4三甲基化（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相关通路，这些通路在各年龄段急性髓系白血病（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，以及多个表观遗传调控因子与关键造血转录因子（如KLF6、BCL6与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，同时引发重现衰老与白血病特征谱的基因表达变化。综上，衰老相关的表观遗传重编程可能构成年龄相关性AML发生的易感状态。