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Chronic β-Cell Depolarization Impairs β-Cell Identity by Disrupting a Network of Ca-Regulated Genes.

Stancill JS, Cartailler JP, Clayton HW, O'Connor JT, Dickerson MT, Dadi PK, Osipovich AB, Jacobson DA, Magnuson MA
Diabetes. 2017 66 (8): 2175-2187

PMID: 28550109 · PMCID: PMC5521870 · DOI:10.2337/db16-1355

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

© 2017 by the American Diabetes Association.

MeSH Terms (18)

Animals Basic Helix-Loop-Helix Transcription Factors Calcium Calcium Signaling Cell Adhesion Cell Cycle Proteins Cell Lineage Cell Polarity Gene Expression Gene Expression Regulation Insulin-Secreting Cells KATP Channels Mice Pancreatic Polypeptide-Secreting Cells S100 Calcium-Binding Protein A4 S100 Calcium Binding Protein A6 S100 Proteins Sulfonylurea Receptors

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