Chronic β-Cell Depolarization Impairs β-Cell Identity by Disrupting a Network of Ca²⁺-Regulated Genes

We used mice lacking Abcc8, a key component of the β-cell K_ATP-channel, to analyze the effects of a sustained elevation in the intracellular Ca²⁺ concentration ([Ca²⁺]_i) on β-cell identity and gene expression. Lineage tracing analysis revealed the conversion of β-cells lacking Abcc8 into pancreatic polypeptide cells but not to α- or δ-cells. RNA-sequencing analysis of FACS-purified Abcc8 β-cells confirmed an increase in Ppy gene expression and revealed altered expression of more than 4,200 genes, many of which are involved in Ca²⁺ signaling, the maintenance of β-cell identity, and cell adhesion. The expression of S100a6 and S100a4, two highly upregulated genes, is closely correlated with membrane depolarization, suggesting their use as markers for an increase in [Ca²⁺]_i Moreover, a bioinformatics analysis predicts that many of the dysregulated genes are regulated by common transcription factors, one of which, Ascl1, was confirmed to be directly controlled by Ca²⁺ influx in β-cells. Interestingly, among the upregulated genes is Aldh1a3, a putative marker of β-cell dedifferentiation, and other genes associated with β-cell failure. Taken together, our results suggest that chronically elevated β-cell [Ca²⁺]_i in Abcc8 islets contributes to the alteration of β-cell identity, islet cell numbers and morphology, and gene expression by disrupting a network of Ca²⁺-regulated genes.