Diabetes-induced trained immunity contributes to the development of atherosclerosis and its complications. This study aimed to investigate in humans whether epigenetic signals involved in immune cell activation and inflammation are initiated in hematopoietic stem/progenitor cells (HSPCs) and transferred to differentiated progeny. High glucose (HG)-exposure of cord blood (CB)-derived HSPCs induced a senescent-associated secretory phenotype (SASP) characterized by cell proliferation lowering, ROS production, telomere shortening, up-regulation of p21 and p27genes, upregulation of NFkB-p65 transcription factor and increased secretion of the inflammatory cytokines TNFα and IL6. Chromatin immunoprecipitation assay (ChIP) of p65 promoter revealed that H3K4me1 histone mark accumulation and methyltransferase SetD7 recruitment, along with the reduction of repressive H3K9me3 histone modification, were involved in NFkB-p65 upregulation of HG-HSPCs, as confirmed by increased RNA polymerase II engagement at gene level. The differentiation of HG-HSPCs into myeloid cells generated highly responsive monocytes, mainly composed of intermediate subsets (CD14hiCD16+), that like the cells from which they derive, were characterized by SASP features and similar epigenetic patterns at the p65 promoter. The clinical relevance of our findings was confirmed in sternal BM-derived HSPCs of T2DM patients. In line with our in vitro model, T2DM HSPCs were characterized by SASP profile and SETD7 upregulation. Additionally, they generated, after myeloid differentiation, senescent monocytes mainly composed of proinflammatory intermediates (CD14hiCD16+) characterized by H3K4me1 accumulation at NFkB-p65 promoter. Hyperglycemia induces marked chromatin modifications in HSPCs, which, once transmitted to the cell progeny, contributes to persistent and pathogenic changes in immune cell function and composition.

中文翻译：

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持续的表观遗传信号促进糖尿病患者 CD34+ 造血干细胞的衰老相关分泌表型和训练的先天免疫

糖尿病引起的免疫力训练有助于动脉粥样硬化及其并发症的发展。本研究旨在研究人类中参与免疫细胞激活和炎症的表观遗传信号是否在造血干/祖细胞 (HSPC) 中启动并转移到分化的后代。脐带血 (CB) 来源的 HSPC 暴露于高葡萄糖 (HG) 会诱导衰老相关的分泌表型 (SASP)，其特征是细胞增殖降低、ROS 产生、端粒缩短、p21 和 p27 基因上调、NFkB 上调p65 转录因子和炎症细胞因子 TNFα 和 IL6 的分泌增加。 p65 启动子的染色质免疫沉淀分析 (ChIP) 显示，H3K4me1 组蛋白标记积累和甲基转移酶 SetD7 招募，以及抑制性 H3K9me3 组蛋白修饰的减少，参与了 HG-HSPC 的 NFkB-p65 上调，RNA 聚合酶 II 参与增加证实了这一点在基因水平上。 HG-HSPC 分化为骨髓细胞产生了高度反应性的单核细胞，主要由中间亚群 (CD14hiCD16+) 组成，与它们来源的细胞一样，具有 SASP 特征和 p65 启动子处类似的表观遗传模式。我们的研究结果的临床相关性在 T2DM 患者的胸骨 BM 衍生的 HSPC 中得到了证实。与我们的体外模型一致，T2DM HSPC 的特征是 SASP 谱和 SETD7 上调。此外，在骨髓分化后，它们产生了主要由促炎中间体（CD14hiCD16+）组成的衰老单核细胞，其特征是H3K4me1在NFkB-p65启动子处积累。高血糖会诱导 HSPC 中显着的染色质修饰，这种修饰一旦传递给细胞后代，就会导致免疫细胞功能和组成的持续致病性变化。