Background and Aims Hyperglycaemia during gestational diabetes (GD) predisposes women and their offspring to later cardiometabolic disease. The hyperglycaemia-mediated epigenetic changes remain to be elucidated. Methyltransferase MLL1-induced trimethylation of histone 3 at lysine 4 (H3K4me3) activates inflammatory and oxidative phenotype. This epigenetic mark in GD women and its transmission to the offspring were investigated. Methods Peripheral blood mononuclear cells (PBMC) were collected from GD and control (C) women and also from adolescents born to women of both groups. Endothelial human umbilical vein endothelial cells (HUVEC) and cord blood mononuclear cells (CBMC) were from umbilical cords. The NF-κBp65 and NOX4 expressions were investigated by reverse transcription quantitative polymerase chain reaction and immunofluorescence (IF). MLL1 and H3K4me3 were investigated by immunoblotting and IF. H3K4me3 on NF-κBp65 and NOX4 promoters was studied by chromatin immunoprecipitation. Superoxide anion generation was measured by electron spin resonance spectroscopy. Plasma cytokines were measured by enzyme-linked immunosorbent assay. To investigate the role of MLL1, HUVEC were exposed to inhibitor MM102 or siRNA transfection. Results PBMC, CBMC, and HUVEC showed an increase of NF-κBp65, IL-6, ICAM-1, MCP-1, and VCAM-1 mRNAs. These findings were associated with H3K4me3 enrichment in the promoter of NF-κBp65. Elevated H3K4me3 and cytokine levels were observed in GD adolescents. MLL1 drives H3K4me3 not only on NF-kB p65, but also on NOX4 promoter. Inhibition of MLL1 blunted NF-κBp65 and NOX4 by modulating inflammatory and oxidative phenotype. Conclusions Such proof-of-concept study shows persistence of MLL1-dependent H3K4me3 in offspring born to GD women, suggesting an epigenetic-driven transmission of maternal phenotype. These findings may pave the way for pharmacological reprogramming of adverse histone modifications to mitigate abnormal phenotypes underlying early ASCVD.

中文翻译：

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妊娠糖尿病的炎症和氧化表型通过表观遗传传递给后代：甲基转移酶 MLL1 诱导的 H3K4me3 的作用


背景和目的 妊娠糖尿病 （GD） 期间的高血糖使妇女及其后代易患晚期心脏代谢疾病。高血糖介导的表观遗传变化仍有待阐明。甲基转移酶 MLL1 诱导的组蛋白 3 赖氨酸 4 位点三甲基化 （H3K4me3） 激活炎症和氧化表型。研究了 GD 女性的这种表观遗传标记及其向后代的传播。方法 收集 GD 和对照 （C） 妇女以及两组妇女所生青少年的外周血单核细胞 （PBMC）。人脐静脉内皮细胞 （HUVEC） 和脐带血单核细胞 （CBMC） 来自脐带。通过逆转录定量聚合酶链反应和免疫荧光 （IF） 检测 NF-κBp65 和 NOX4 的表达。通过免疫印迹和 IF 研究 MLL1 和 H3K4me3。通过染色质免疫沉淀研究 H3K4me3 对 NF-κBp65 和 NOX4 启动子的影响。通过电子自旋共振光谱法测量超氧阴离子的产生。通过酶联免疫吸附测定法测定浆细胞因子。为了研究 MLL1 的作用，将 HUVEC 暴露于抑制剂 MM102 或 siRNA 转染。结果 PBMC 、 CBMC 和 HUVEC 显示 NF-κBp65 、 IL-6 、 ICAM-1 、 MCP-1 和 VCAM-1 mRNAs 增加。这些发现与 NF-κBp65 启动子中 H3K4me3 的富集有关。在 GD 青少年中观察到 H3K4me3 和细胞因子水平升高。MLL1 不仅在 NF-kB p65 上驱动 H3K4me3，而且在 NOX4 启动子上驱动 H3K4me3。抑制 MLL1 通过调节炎症和氧化表型减弱 NF-κBp65 和 NOX4。 结论 这种概念验证研究表明，MLL1 依赖性 H3K4me3 在 GD 女性所生的后代中持续存在，表明母体表型的表观遗传驱动传递。这些发现可能为不良组蛋白修饰的药理学重编程铺平道路，以减轻早期 ASCVD 的异常表型。