| First Author | Stancill JS | Year | 2017 |
| Journal | Diabetes | Volume | 66 |
| Issue | 8 | Pages | 2175-2187 |
| PubMed ID | 28550109 | Mgi Jnum | J:249474 |
| Mgi Id | MGI:5923522 | Doi | 10.2337/db16-1355 |
| Citation | Stancill JS, et al. (2017) Chronic beta-Cell Depolarization Impairs beta-Cell Identity by Disrupting a Network of Ca2+-Regulated Genes. Diabetes 66(8):2175-2187 |
| abstractText | We used mice lacking Abcc8, a key component of the beta-cell KATP-channel, to analyze the effects of a sustained elevation in the intracellular Ca2+ concentration ([Ca2+]i) on beta-cell identity and gene expression. Lineage tracing analysis revealed the conversion of beta-cells lacking Abcc8 into pancreatic polypeptide cells but not to alpha- or delta-cells. RNA-sequencing analysis of FACS-purified Abcc8-/- beta-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 beta-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 beta-cells. Interestingly, among the upregulated genes is Aldh1a3, a putative marker of beta-cell dedifferentiation, and other genes associated with beta-cell failure. Taken together, our results suggest that chronically elevated beta-cell [Ca2+]i in Abcc8-/- islets contributes to the alteration of beta-cell identity, islet cell numbers and morphology, and gene expression by disrupting a network of Ca2+-regulated genes. |
