衰老与人类基因启动子区DNA甲基化（DNAm）异常增加有关，包括骨髓干细胞。在血液系统恶性肿瘤如急性髓系白血病中，DNAm模式进一步受到了干扰，但这些表观遗传变化的生理意义尚未知晓。通过对人类干/祖细胞（HSPCs）进行表观遗传编辑，我们发现p15甲基化影响体内造血功能。我们使用dCas9-3A3L编辑了CDKN2B（p15）启动子和ARF（p14），观察到DNAm扩散超过gRNA位置。我们发现，尽管是短暂的递送系统，DNAm在体外的髓系分化过程中仍能维持，并且p15启动子的高甲基化会降低基因的表达。在体内，编辑的人类HSPCs能够在小鼠的骨髓中移植，并且定向DNAm能够长期维持在HSPCs中。此外，这些表观遗传变化在髓系和淋巴系细胞系谱中具有保守性和遗传性。尽管单核细胞（CD14+）和粒细胞（CD66b+）的数量不受影响，亦即髓系（CD33+）和淋巴系（CD19+）细胞的比例不受影响，p15高甲基化HSPCs移植小鼠中单核细胞数量减少，粒细胞数量增加。从p15高甲基化HSPCs分化的单核细胞似乎被激活，并显示出增加的炎症转录程序。我们认为这些发现在临床上具有相关性，因为我们在患有克隆性造血系统的患者外周血中发现了p15启动子甲基化。我们的研究表明DNAm可以定向和维持在人类HSPCs中，并证明了p15位点异常DNAm的功能相关性。因此，其他与衰老相关的异常DNAm可能会影响体内的造血功能。

Aging is associated with an abnormal increase in DNA methylation (DNAm) in human gene promoters, including in bone marrow stem cells. DNAm patterns are further perturbed in hematological malignancies such as acute myeloid leukemia but the physiological significance of such epigenetic changes is unknown. Using epigenetic editing of human stem/progenitor cells (HSPCs), we show that p15 methylation affects hematopoiesis in vivo. We edited the CDKN2B (p15) promoter and ARF (p14) using dCas9-3A3L and observed DNAm spreading beyond the gRNA location. We find that despite a transient delivery system, DNAm is maintained during myeloid differentiation in vitro, and hypermethylation of the p15 promoter reduces gene expression. In vivo, edited human HSPCs can engraft the bone marrow of mice and targeted DNAm is maintained in HSPCs long term. Moreover, epigenetic changes are conserved and inherited in both myeloid and lymphoid lineages. Although the proportion of myeloid (CD33+) and lymphoid (CD19+) cells is unaffected, monocyte (CD14+) populations decreased and granulocytes (CD66b+) increased in mice engrafted with p15 hypermethylated HSPCs. Monocytes derived from p15 hypermethylated HSPCs appear to be activated and show increased inflammatory transcriptional programs. We believe these findings have clinical relevance since we found p15 promoter methylation in the peripheral blood of patients with clonal hematopoiesis. Our study shows DNAm can be targeted and maintained in human HSPCs and demonstrated functional relevance of aberrant DNAm on the p15 locus. As such, other aging-associated aberrant DNAm may impact hematopoiesis in vivo.