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Am J Physiol Endocrinol Metab. 2018 Dec 11. doi: 10.1152/ajpendo.00229.2018. [Epub ahead of print]

Transgene-associated hGH expression in pancreatic β-cells impairs identification of sex-based gene expression differences.

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Cell and Developmental Biology, Vanderbilt University School of Medicine.
Molecular Physiology and Biophysics, Vanderbilt University School of Medicine.
Center for Stem Cell Biology, Vanderbilt University School of Medicine.
Center for Stem Cell Biology, Vanderbilt University School of Medicine, United States.


Fluorescence protein reporter genes are widely used to identify and sort murine pancreatic ß-cells. In this study we compared use of the MIP-GFP transgene, which exhibits aberrant expression of human growth hormone (hGH), with a newly derived Ins2Apple allele that lacks hGH expression on the expression of sex-specific genes. ß-cells from MIP-GFP transgenic mice exhibit changes in the expression of 7,733 genes, or greater than half of their transcriptome, when compared to ß-cells from Ins2Apple/+ mice. To determine how these differences might affect a typical differential gene expression study, we analyzed the effect of sex on gene expression using both reporter lines. 657 differentially-expressed genes were identified between male and female ß-cells containing the Ins2Apple allele. Female ß-cells exhibit higher expression of Xist, Tmed9, Arpc3, Eml2 and several islet-enriched transcription factors, including Nkx2-2 and Hnf4a, whereas male ß-cells exhibited a generally higher expression of genes involved in cell cycle regulation. In marked contrast, the same male versus female comparison of ß-cells containing the MIP-GFP transgene revealed only 115 differentially-expressed genes, and comparison of the two lists of differentially expressed genes revealed only 17 that were common to both analyses. These results indicate 1) that male and female ß-cells differ in their expression of key transcription factors and cell cycle regulators, and 2) that the MIP-GFP transgene may attenuate sex-specific differences that distinguish male and female ß-cells, thereby impairing the identification of sex-specific variations.


Pancreatic β-cells; RNA-seq; gene expression; growth hormone; sex


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