Faculty Opinions recommendation of Identification of insulin signaling elements in human beta-cells: autocrine regulation of insulin gene expression.

AbstractMitochondrial gene expression is pivotal to cell metabolism. Nevertheless, it is unknown whether it diverges within a given cell type. Here, we analysed single-cell RNA-seq experiments from ∼4600 human pancreatic alpha and beta cells, as well as ∼900 mouse beta cells. Cluster analysis revealed two distinct human beta cells populations, which diverged by mitochondrial (mtDNA) and nuclear DNA (nDNA)-encoded oxidative phosphorylation (OXPHOS) gene expression in healthy and diabetic individuals, and in newborn but not in adult mice. Insulin gene expression was elevated in beta cells with higher mtDNA gene expression in humans and in young mice. Such human beta cell populations also diverged in mt-RNA mutational repertoire, and in their selective signature, thus implying the existence of two previously overlooked distinct and conserved beta cell populations. While applying our approach to alpha cells, two sub-populations of cells were identified which diverged in mtDNA gene expression, yet these cellular populations did not consistently diverge in nDNA OXPHOS genes expression, nor did they correlate with the expression of glucagon, the hallmark of alpha cells. Thus, pancreatic beta cells within an individual are divided into distinct groups with unique metabolic-mitochondrial signature.

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Oxidative Stress-mediated, Post-translational Loss of MafA Protein as a Contributing Mechanism to Loss of Insulin Gene Expression in Glucotoxic Beta Cells

Journal of Biological Chemistry ◽

10.1074/jbc.m410345200 ◽

2005 ◽

Vol 280 (12) ◽

pp. 11107-11113 ◽

Cited By ~ 135

Author(s):

Jamie S. Harmon ◽

Roland Stein ◽

R. Paul Robertson

Keyword(s):

Oxidative Stress ◽

Gene Expression ◽

Beta Cells ◽

Insulin Gene ◽

Insulin Gene Expression

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Differentially expressed Maf family transcription factors, c-Maf and MafA, activate glucagon and insulin gene expression in pancreatic islet alpha- and beta-cells

Journal of Molecular Endocrinology ◽

10.1677/jme.0.0320009 ◽

2004 ◽

Vol 32 (1) ◽

pp. 9-20 ◽

Cited By ~ 53

Author(s):

K Kataoka ◽

S Shioda ◽

K Ando ◽

K Sakagami ◽

H Handa ◽

...

Keyword(s):

Gene Expression ◽

Transcription Factors ◽

Cell Line ◽

Beta Cells ◽

Cell Lines ◽

Promoter Activity ◽

Insulin Gene ◽

Insulinoma Cell ◽

Insulin Gene Expression ◽

Glucagon And Insulin

A basic-leucine zipper transcription factor, MafA, was recently identified as one of the most important transactivators of insulin gene expression. This protein controls the glucose-regulated and pancreatic beta-cell-specific expression of the insulin gene through a cis-regulatory element called RIPE3b/MARE (Maf-recognition element). Here, we show that MafA expression is restricted to beta-cells of pancreatic islets in vivo and in insulinoma cell lines. We also demonstrate that c-Maf, another member of the Maf family of transcription factors, is expressed in islet alpha-cells and in a glucagonoma cell line (alphaTC1), but not in gamma- and delta-cells. An insulinoma cell line, betaTC6, also expressed c-Maf, albeit at a low level. Chromatin immunoprecipitation assays demonstrated that Maf proteins associate with insulin and glucagon promoters in beta- and alpha-cell lines, respectively. c-Maf protein stimulated glucagon promoter activity in a transient luciferase assay, and activation of the glucagon promoter by c-Maf was more efficient than by the other alpha-cell-enriched transcription factors, Cdx2, Pax6, and Isl-1. Furthermore, inhibition of c-Maf expression in alphaTC1 cells by specific short hairpin RNA resulted in marked reduction of the glucagon promoter activity. Thus, c-Maf and MafA are differentially expressed in alpha- and beta-cells where they regulate glucagon and insulin gene expression, respectively.

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