Dynamic Ca2+-dependent transcription links metabolic stress to impaired ß-cell identity

Sustained stimulation and elevations in intracellular Ca2+ concentrations due to metabolic stress in pre-diabetic states triggers gene expression changes contributing to the loss of pancreatic ß-cell function. To establish a temporal relationship between ß-cell stimulation and perturbations in Ca2+-dependent transcription, islet Ca2+ dynamics and gene expression was analysed in cultured mouse islets that were stimulated by membrane depolarization with tolbutamide, a sulfonylurea that blocks the ATP-dependent potassium (KATP) channel. By varying the timing and nature of the experimental stimulory conditions, we defined temporal transcriptional dynamics of islets in responce to stimulation, identified immediate early response genes and transcriptional regulators that drive these transcriptional changes and defined a set of physiologically relevant Ca2+-regulated genes with sustained changes 24 hours post-stimulation. Ca2+-dependent changes resulting from chronic stimulation include an increase in ß-cell stress response and dedifferentiation genes, and a decrease in critical ß-cell identity genes.

前驱糖尿病状态下，代谢应激引发的持续刺激与细胞内钙离子（Ca²+）浓度升高，可触发基因表达改变，进而导致胰腺β细胞（pancreatic β-cell）功能丧失。为明确β细胞刺激与钙离子依赖转录紊乱之间的时间关联，研究团队对经膜去极化刺激的培养小鼠胰岛开展了胰岛钙离子动态变化与基因表达分析：该刺激采用磺酰脲类药物甲苯磺丁脲（tolbutamide），其可阻断ATP敏感性钾（KATP）通道。通过调整实验刺激条件的时序与类型，本研究明确了胰岛受刺激后的时间依赖性转录动态特征，鉴定出驱动此类转录改变的即刻早期应答基因与转录调控因子，并筛选出一批在刺激后24小时仍存在持续表达变化的生理相关钙离子调控基因。慢性刺激引发的钙离子依赖表达改变包括β细胞应激应答基因与去分化基因的表达上调，以及关键β细胞特征基因的表达下调。