Examinining the myelin transcription factor dependent genes in islet beta cells under euglycemia

A hallmark of type 2 diabetes (T2D) is endocrine islet beta-cell failure, which can occur via cell dysfunction, loss-of-identity, and/or death. How each is induced remains largely unknown. Here, we use mouse beta-cells that are deficient for Myelin transcription factors (Myt TFs, including Myt1, 2, and 3) to address this question. We have reported that inactivating all three Myt genes in pancreatic progenitor cells (MytPancD) causes beta-cell failure and late onset diabetes in mice. Their lower expression in human beta-cells is correlated with beta-cell dysfunction and SNPs in Myt2 and Myt3 are associated in higher risk of T2D. We now show that these Myt TF-deficient beta-cells also de-differentiate by reactivating several progenitor markers, assayed by both immuno-assays and RNAseq. Intriguingly, mosaic Myt TF inactivation in only a portion of islet beta-cells does not results in overt diabetes, but this creates a condition where Myt TF-deficient beta-cells stay alive while dedifferentiating and trans-differentiating into Ppy-expressing cells. By transplanting MytPancD islets into the anterior eye chambers of immune-compromised mice, we directly show that glycemic and obesity-related conditions influence cell fate. These findings suggest that the observed beta-cell defects in T2D depend on not only their inherent genetic/epigenetic defects, but also the metabolic load. Control and mutant beta cells from 2-months old mice were purified, RNA prepared, and sequenced. Note that the raw data of the control samples, done at the same time as the mutants, were deposited in Array-Express under the submission number: E-MTAB-2266.