Diabetes-associated MYT1 and ST18 regulate human b-cell insulin secretion and survival via other diabetes-risk genes

Genetic and environmental factors together cause islet beta-cell failure, leading to Type 2 diabetes (T2D). Here, we study how two members of the Myelin transcription factor family (MYT1, MYT1L, and ST18) prevent human beta-cell failure under obesity-related stress. We have reported that these factors are induced by high levels of obesity-related nutrients. They prevent beta-cell failure in mouse islets and human beta-cell lines. Their variants are all associated with human T2D, and their downregulation accompanies beta-cell dysfunction during T2D development. By knocking down MYT1 or ST18 separately in primary human donor islets, we show here that they have overlapping but distinct functions. Under normal culture conditions, MYT1-knockdown (KD) causes beta-cell death, while ST18-KD compromises glucose-stimulated insulin secretion. Under obesity-induced metabolic stress in vivo, ST18-KD also causes beta-cell death. These findings led us to explore the molecular mechanisms by which MUYT1/ST18 regulate beta cells. The data presented here are the RNAseq of human islet beta cells with knockdown of these factors. Overall design: MYT1 or ST18 were knocked down in primary human beta cells using shRNA, made as pseudo-islets. Gene expression in resulting cells were examined with scRNA-seq uisng the In-Drop platform.

遗传与环境因素共同导致胰岛β细胞功能衰竭，进而引发2型糖尿病（Type 2 Diabetes，简称T2D）。本研究聚焦于髓磷脂转录因子家族的两个成员（MYT1、MYT1L与ST18），探究它们在肥胖相关应激条件下如何保护人类胰岛β细胞免于衰竭。本团队此前已报道，这类因子可被高水平的肥胖相关营养物质诱导表达；它们能够在小鼠胰岛与人类β细胞系中阻止β细胞衰竭。这些因子的变异均与人类T2D相关，且在T2D发病进程中，它们的表达下调会伴随β细胞功能异常。本研究通过在原代人类供体胰岛中分别敲低MYT1或ST18，证实二者功能存在重叠但又各具特异性：在常规培养条件下，MYT1敲低（KD）会导致β细胞死亡，而ST18敲低（KD）则会损害葡萄糖刺激的胰岛素分泌功能；在体内肥胖诱导的代谢应激条件下，ST18-KD同样会引发β细胞死亡。上述发现促使我们探究MYT1/ST18调控β细胞的分子机制。本数据集包含经上述因子敲低处理的人类胰岛β细胞的RNA测序（RNA-sequencing，简称RNAseq）数据。实验整体设计：通过短发夹RNA（short hairpin RNA，简称shRNA）在原代人类β细胞中敲低MYT1或ST18，并将其制备为伪胰岛；随后采用In-Drop平台通过单细胞RNA测序（single-cell RNA-sequencing，简称scRNA-seq）检测所得细胞的基因表达情况。