Unknown,Transcriptomics,Genomics,Proteomics

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Expression data from E15.5 mouse embryos

ABSTRACT: The pancreatic beta cells are the only cells that can produce insulin in response to prevailing glycemia. The development of beta cells was found to be depending on the activity of a complex genetic network. Overexpression of transcriptional factor MafK in beta cells have resulted in impairment of thier functions and suppressed insulin secretion and increased the severity of beta cell loss resulting in an overt diabetes. We used microarrays to study the changes in islet gene expression profiles in MafK Tg. Mafk overexpression was expected to disrupt functions of genes containing MARE sites in their regulatory regions by bindig to cis-regulatory elements. Exploration of new factors with sunctional MAREs in thier regulatory regions in beta cells will improve our targeting stratigies for treatment of diabetes. A 0.78 kb full-length cDNA encoding the murine MafK protein including a FLAG peptide at the N-terminus was inserted into the rat insulin I promoter. Then, the construct was injected into BDF1-fertilized eggs to generate transgenic mice. All Tg mice were maintained on an ICR genetic background. Whole pancreata were collected from MafK transgenic embryos as well as wild type embryos at E15.5 (N=3 per each gentype). Total RNA was extracted and hybridized for Affymetrix microarray analysis.

ORGANISM(S): Mus musculus

SUBMITTER: Ahmed Abdellatif

PROVIDER: E-GEOD-62834 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Insulin resistance is necessary but not sufficient for the development of type 2 diabetes. Diabetes results when pancreatic beta-cells fail to compensate for insulin resistance by increasing insulin production through an expansion of beta-cell mass or increased insulin secretion. Communication between insulin target tissues and beta-cells may initiate this compensatory response. Correlated changes in gene expression between tissues can provide evidence for such intercellular communication. We profiled gene expression in six tissues of mice from an obesity-induced diabetes-resistant and a diabetes-susceptible strain before and after the onset of diabetes. We studied the correlation structure of mRNA abundance and identified 105 co-expression gene modules. We provide an interactive gene network model showing the correlation structure between the expression modules within and among the six tissues. This resource also provides a searchable database of gene expression profiles for all genes in six tissues in lean and obese diabetes-resistant and diabetes-susceptible mice, at 4 and 10 weeks of age. A cell cycle regulatory module in islets predicts diabetes susceptibility. The module predicts islet replication; we found a strong correlation between ^2 H_2 O incorporation into islet DNA /in vivo/ and the expression pattern of the cell cycle module. This pattern is highly correlated with that of several individual genes in insulin target tissues, including IGF2, which has been shown to promote beta-cell proliferation, suggesting that these genes may provide a link between insulin resistance and beta-cell proliferation. Keywords: time course, mouse strain comparison, effect of obesity, Type 2 diabetes is a disorder that involves an increased demand for insulin brought about by insulin resistance, together with a failure to compensate with sufficient insulin production. Although Insulin resistance occurs in most obese individuals, diabetes is generally forestalled through compensation with increased insulin. This increase in insulin occurs through an expansion of beta-cell mass and/or increased insulin secretion by individual beta-cells. Failure to compensate for insulin resistance leads to type 2 diabetes. One way to understand the pathophysiology of diabetes is to examine the coordinate changes in gene expression that occur in insulin-responsive tissues and pancreatic islets in obese animals that either compensate for insulin resistance or progress to type 2 diabetes. In each case, there are groups of genes that undergo changes in expression in a highly correlated fashion. By identifying groups of correlated transcripts (gene expression modules) during the compensation and development of diabetes, we can gain insight into potential pathways and regulatory networks in obesity-induced diabetes. We study two strains of mice that differ in obesity-induced diabetes susceptibility. In this study, we surveyed gene expression in six tissues of lean and obese C57BL/6 (B6) and BTBR mice aged 4 wks and 10 wks. B6 mice remain essentially non-diabetic at all ages, irrespective of obesity. When obese, BTBR mice become severely diabetic by 10 weeks of age. By analyzing the correlation structure of the genes under three contrast conditions, obesity, strain, and age, we identified gene expression modules associated with the onset of diabetes and provide an interactive co-expression network model of type 2 diabetes. We found a key module that is comprised of cell cycle regulatory genes. In the islet, the expression profile of these transcripts accurately predicts diabetes and is highly correlated with islet cell proliferation.

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Expression data from E15.5 mouse embryos

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