Diabetes Research Group, British Columbia Children's Hospital Research Institute, Vancouver, BC, Canada.
Department of Surgery, University of British Columbia, Vancouver, BC, Canada.
Diabetologia. 2023 Jun;66(6):1097-1115. doi: 10.1007/s00125-023-05896-6. Epub 2023 Mar 13.
AIMS/HYPOTHESIS: Beta cells control glucose homeostasis via regulated production and secretion of insulin. This function arises from a highly specialised gene expression programme that is established during development and then sustained, with limited flexibility, in terminally differentiated cells. Dysregulation of this programme is seen in type 2 diabetes but mechanisms that preserve gene expression or underlie its dysregulation in mature cells are not well resolved. This study investigated whether methylation of histone H3 lysine 4 (H3K4), a marker of gene promoters with unresolved functional importance, is necessary for the maintenance of mature beta cell function.
Beta cell function, gene expression and chromatin modifications were analysed in conditional Dpy30 knockout mice, in which H3K4 methyltransferase activity is impaired, and in a mouse model of diabetes.
H3K4 methylation maintains expression of genes that are important for insulin biosynthesis and glucose responsiveness. Deficient methylation of H3K4 leads to a less active and more repressed epigenome profile that locally correlates with gene expression deficits but does not globally reduce gene expression. Instead, developmentally regulated genes and genes in weakly active or suppressed states particularly rely on H3K4 methylation. We further show that H3K4 trimethylation (H3K4me3) is reorganised in islets from the Lepr mouse model of diabetes in favour of weakly active and disallowed genes at the expense of terminal beta cell markers with broad H3K4me3 peaks.
CONCLUSIONS/INTERPRETATION: Sustained methylation of H3K4 is critical for the maintenance of beta cell function. Redistribution of H3K4me3 is linked to gene expression changes that are implicated in diabetes pathology.
目的/假设：β 细胞通过调节胰岛素的产生和分泌来控制葡萄糖稳态。这种功能源自于高度特化的基因表达程序，该程序在发育过程中建立，然后在终末分化的细胞中以有限的灵活性维持。该程序的失调见于 2 型糖尿病，但在成熟细胞中保留基因表达或导致其失调的机制尚未得到很好的解决。本研究探讨了组蛋白 H3 赖氨酸 4（H3K4）的甲基化是否是维持成熟β细胞功能所必需的，H3K4 是未解决功能重要性的基因启动子的标志。
在条件性 Dpy30 敲除小鼠和糖尿病小鼠模型中分析了β细胞功能、基因表达和染色质修饰。
H3K4 甲基化维持了胰岛素生物合成和葡萄糖反应性重要基因的表达。H3K4 甲基化的缺陷导致了更不活跃和更受抑制的表观基因组谱，该谱与基因表达缺陷局部相关，但不会全局降低基因表达。相反，发育调节基因和处于弱活性或抑制状态的基因特别依赖于 H3K4 甲基化。我们还表明，H3K4 三甲基化（H3K4me3）在糖尿病 Lepr 小鼠模型的胰岛中重新组织，有利于弱活性和被禁止的基因，而牺牲具有广泛 H3K4me3 峰的终末β细胞标记物。
结论/解释：H3K4 的持续甲基化对于维持β细胞功能至关重要。H3K4me3 的重分布与糖尿病发病机制中涉及的基因表达变化有关。
