- Stancill JS, Cartailler JP, Clayton HW, O'Connor JT, Dickerson MT, Dadi PK, Osipovich AB, Jacobson DA, Magnuson MA. Chronic β-Cell Depolarization Impairs β-Cell Identity by Disrupting a Network of Ca(2+)-Regulated Genes. Diabetes. 2017 May 26. PMID: 28550109 [PubMed].
We used mice lacking Abcc8, a key component of the β-cell KATP-channel, to analyze the effects of a sustained elevation in the intracellular Ca(2+) concentration ([Ca(2+)]i) on β-cell identity and gene expression. Lineage tracing analysis revealed the conversion of β-cells lacking Abcc8 into PP-cells, but not to α- or δ-cells. RNA-Seq analysis of FACS-purified Abcc8(-/-) β-cells confirmed an increase in Ppy gene expression, and revealed altered expression of over 4,200 genes, many of which are involved in Ca(2+)-signaling, the maintenance of β-cell identity, and cell adhesion. The expression of S100a6 and S100a4, two highly up-regulated genes, is closely correlated with membrane depolarization, suggesting their use as markers for an increase in [Ca(2+)]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 Ca(2+) influx in β-cells. Interestingly, among the upregulated genes is Aldh1a3, a putative marker of β-cell de-differentiation, and other genes associated with β-cell failure. Taken together, our results suggest that chronically-elevated β-cell [Ca(2+)]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 Ca(2+)-regulated genes.