Department of Diabetes, Central Clinical School, Monash University, Melbourne, Victoria, 3004, Australia.
Epigenetics in Human Health and Disease Laboratory, Central Clinical School, Monash University, Melbourne, Victoria, 3004, Australia.
Signal Transduct Target Ther. 2022 Jul 22;7(1):248. doi: 10.1038/s41392-022-01034-7.
Type 1 diabetes (T1D) is an autoimmune disease that selectively destroys insulin-producing β-cells in the pancreas. An unmet need in diabetes management, current therapy is focussed on transplantation. While the reprogramming of progenitor cells into functional insulin-producing β-cells has also been proposed this remains controversial and poorly understood. The challenge is determining why default transcriptional suppression is refractory to exocrine reactivation. After the death of a 13-year-old girl with established insulin-dependent T1D, pancreatic cells were harvested in an effort to restore and understand exocrine competence. The pancreas showed classic silencing of β-cell progenitor genes with barely detectable insulin (Ins) transcript. GSK126, a highly selective inhibitor of EZH2 methyltransferase activity influenced H3K27me3 chromatin content and transcriptional control resulting in the expression of core β-cell markers and ductal progenitor genes. GSK126 also reinstated Ins gene expression despite absolute β-cell destruction. These studies show the refractory nature of chromatin characterises exocrine suppression influencing β-cell plasticity. Additional regeneration studies are warranted to determine if the approach of this n-of-1 study generalises to a broader T1D population.
1 型糖尿病（T1D）是一种自身免疫性疾病，它会选择性地破坏胰腺中的胰岛素分泌β细胞。目前的治疗方法主要集中在移植上，但这并不能满足糖尿病管理的需求。虽然已经提出将祖细胞重编程为功能性胰岛素分泌β细胞，但这仍然存在争议，并且了解甚少。挑战在于确定为什么默认的转录抑制对外分泌重新激活有抗性。在一名患有确诊的胰岛素依赖型 T1D 的 13 岁女孩去世后，人们努力从其胰腺中提取细胞，以恢复和了解外分泌功能。胰腺显示出β细胞祖基因的经典沉默，几乎检测不到胰岛素（Ins）转录物。GSK126 是一种高度选择性的 EZH2 甲基转移酶活性抑制剂，可影响 H3K27me3 染色质含量和转录控制，从而导致核心β细胞标志物和导管祖细胞基因的表达。尽管β细胞已被完全破坏，但 GSK126 也恢复了 Ins 基因的表达。这些研究表明，染色质的难治性特征会影响外分泌抑制和β细胞的可塑性。需要进一步的再生研究来确定这种 1 对 1 研究的方法是否适用于更广泛的 T1D 人群。
