Chronic β-Cell Depolarization Impairs β-Cell Identity by Disrupting a Network of Ca-Regulated Genes.
AUTHORS
- PMID: 28550109 [PubMed].
- PMCID: PMC5521870.
ABSTRACT
We used mice lacking, a key component of the β-cell K-channel, to analyze the effects of a sustained elevation in the intracellular Caconcentration ([Ca]) on β-cell identity and gene expression. Lineage tracing analysis revealed the conversion of β-cells lackinginto pancreatic polypeptide cells but not to α- or δ-cells. RNA-sequencing analysis of FACS-purifiedβ-cells confirmed an increase ingene expression and revealed altered expression of more than 4,200 genes, many of which are involved in Casignaling, the maintenance of β-cell identity, and cell adhesion. The expression ofand, 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 Cainflux 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]inislets contributes to the alteration of β-cell identity, islet cell numbers and morphology, and gene expression by disrupting a network of Ca-regulated genes.
We used mice lacking, a key component of the β-cell K-channel, to analyze the effects of a sustained elevation in the intracellular Caconcentration ([Ca]) on β-cell identity and gene expression. Lineage tracing analysis revealed the conversion of β-cells lackinginto pancreatic polypeptide cells but not to α- or δ-cells. RNA-sequencing analysis of FACS-purifiedβ-cells confirmed an increase ingene expression and revealed altered expression of more than 4,200 genes, many of which are involved in Casignaling, the maintenance of β-cell identity, and cell adhesion. The expression ofand, 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 Cainflux 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]inislets contributes to the alteration of β-cell identity, islet cell numbers and morphology, and gene expression by disrupting a network of Ca-regulated genes.
Tags: 2017