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.