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Transgene-associated human growth hormone expression in pancreatic ?-cells impairs identification of sex-based gene expression differences.

ABSTRACT: Fluorescent protein reporter genes are widely used to identify and sort murine pancreatic ?-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. ?-Cells from MIP-GFP transgenic mice exhibit changes in the expression of 7,733 genes, or greater than half of their transcriptome, compared with ?-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. Six hundred fifty-seven differentially expressed genes were identified between male and female ?-cells containing the Ins2Apple allele. Female ?-cells exhibit higher expression of Xist, Tmed9, Arpc3, Eml2, and several islet-enriched transcription factors, including Nkx2-2 and Hnf4a, whereas male ?-cells exhibited a generally higher expression of genes involved in cell cycle regulation. In marked contrast, the same male vs. female comparison of ?-cells containing the MIP-GFP transgene revealed only 115 differentially expressed genes, and comparison of the 2 lists of differentially expressed genes revealed only 17 that were common to both analyses. These results indicate that 1) male and female ?-cells differ in their expression of key transcription factors and cell cycle regulators and 2) the MIP-GFP transgene may attenuate sex-specific differences that distinguish male and female ?-cells, thereby impairing the identification of sex-specific variations.

SUBMITTER: Stancill JS

PROVIDER: S-EPMC6397359 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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

Stancill Jennifer S JS Osipovich Anna B AB Cartailler Jean-Philippe JP Magnuson Mark A MA

American journal of physiology. Endocrinology and metabolism 20181211 2

Fluorescent protein reporter genes are widely used to identify and sort murine pancreatic β-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 Ins2<sup>Apple</sup> allele that lacks hGH expression on the expression of sex-specific genes. β-Cells from MIP-GFP transgenic mice exhibit changes in the expression of 7,733 genes, or greater than half of their transcriptome, compared with β-cells from Ins ...[more]

PMID: 30532991

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Project description:BACKGROUND:Growth regulation is a complex process influenced by genetic and environmental factors. We examined differences between growth hormone (GH) transgenic (T) and non-transgenic (NT) coho salmon to elucidate whether the same loci were involved in controlling body size and gene expression phenotypes, and to assess whether physiological transformations occurring from GH transgenesis were under the influence of alternative pathways. The following genomic techniques were used to explore differences between size classes within and between transgenotypes (T vs. NT): RNA-Seq/Differentially Expressed Gene (DEG) analysis, quantitative PCR (qPCR) and OpenArray analysis, Genotyping-by-Sequencing, and Genome-Wide Association Study (GWAS). RESULTS:DEGs identified in comparisons between the large and small tails of the size distributions of T and NT salmon (NTLarge, NTSmall, TLarge and TSmall) spanned a broad range of biological processes, indicating wide-spread influence of the transgene on gene expression. Overexpression of growth hormone led to differences in regulatory loci between transgenotypes and size classes. Expression levels were significantly greater in T fish at 16 of 31 loci and in NT fish for 10 loci. Eleven genes exhibited different mRNA levels when the interaction of size and transgenotype was considered (IGF1, IGFBP1, GH, C3-4, FAS, FAD6, GLUT1, G6PASE1, GOGAT, MID1IP1). In the GWAS, 649 unique SNPs were significantly associated with at least one study trait, with most SNPs associated with one of the following traits: C3_4, ELA1, GLK, IGF1, IGFBP1, IGFII, or LEPTIN. Only 1 phenotype-associated SNP was found in common between T and NT fish, and there were no SNPs in common between transgenotypes when size was considered. CONCLUSIONS:Multiple regulatory loci affecting gene expression were shared between fast-growing and slow-growing fish within T or NT groups, but no such regulatory loci were found to be shared between NT and T groups. These data reveal how GH overexpression affects the regulatory responses of the genome resulting in differences in growth, physiological pathways, and gene expression in T fish compared with the wild type. Understanding the complexity of regulatory gene interactions to generate phenotypes has importance in multiple fields ranging from applications in selective breeding to quantifying influences on evolutionary processes.

Dataset Information

Transgene-associated human growth hormone expression in pancreatic ?-cells impairs identification of sex-based gene expression differences.

Publications

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

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