The regenerative capacity of hematopoietic stem cells (HSCs) is limited by the accumulation of DNA damage. Conditional mutagenesis of the histone 3 lysine 4 (H3K4) methyltransferase, Setd1a, revealed that it is required for the expression of DNA damage recognition and repair pathways in HSCs. Specific deletion of Setd1a in adult long-term (LT) HSCs is compatible with adult life and has little effect on the maintenance of phenotypic LT-HSCs in the bone marrow. However, SETD1A-deficient LT-HSCs lose their transcriptional cellular identity, accompanied by loss of their proliferative capacity and stem cell function under replicative stress in situ and after transplantation. In response to inflammatory stimulation, SETD1A protects HSCs and progenitors from activation-induced attrition in vivo. The comprehensive regulation of DNA damage responses by SETD1A in HSCs is clearly distinct from the key roles played by other epigenetic regulators, including the major leukemogenic H3K4 methyltransferase MLL1, or MLL5, indicating that HSC identity and function is supported by cooperative specificities within an epigenetic framework.

中文翻译：

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SETD1A 保护 HSC 免受体内活化诱导的功能衰退

造血干细胞 (HSC) 的再生能力受到 DNA 损伤积累的限制。组蛋白 3 赖氨酸 4 (H3K4) 甲基转移酶 Setd1a 的条件诱变表明，它是 HSC 中 DNA 损伤识别和修复途径表达所必需的。成人长期 (LT) HSC 中 Setd1a 的特定缺失与成年生活相容，对骨髓中表型 LT-HSC 的维持几乎没有影响。然而，SETD1A 缺陷的 LT-HSCs 失去了它们的转录细胞特性，伴随着它们在原位和移植后的复制压力下的增殖能力和干细胞功能的丧失。为响应炎症刺激，SETD1A 保护 HSC 和祖细胞免受体内活化诱导的磨损。