A Syntenic Cross Species Aneuploidy Genetic Screen Links RCAN1 Expression to β-Cell Mitochondrial Dysfunction in Type 2 Diabetes
| Autor: | Ann Becker, Pinar Coskun, Petr Volkov, Vinder Kashmir, Nikolay Oskolkov, Claire F. Jessup, Heshan Peiris, Michael T. Ryan, William C. Mobley, Amanda J Genders, Nicholas M. Morton, Alyce M. Martin, D. Ross Laybutt, Michael D. Duffield, Michael A. Cousin, João Fadista, Jeng Yie Chan, Sean L. McGee, Leif Groop, Alexandros C. Kokotos, Victor L. J. Tybulewicz, Tertius Hough, Elizabeth M. C. Fisher, Melanie April Pritchard, Jorge Busciglio, P. Toby Coates, Roderick N. Carter, Charlotte Ling, Madiha Saiedi, Sijun Yang, Pavel V. Belichenko, Damien J. Keating |
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| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Cancer Research Candidate gene endocrine system diseases Physiology Chromosomes Human Pair 21 medicine.medical_treatment Cell Membranes Muscle Proteins Mitochondrion QH426-470 Biochemistry Mice In-vitro 0302 clinical medicine Endocrinology Adenosine Triphosphate Insulin-Secreting Cells Insulin Secretion Medicine and Health Sciences Glucose homeostasis Insulin Genetics (clinical) Energy-Producing Organelles Regulation of gene expression Genetics & Heredity DNA methylation Organic Compounds Monosaccharides Intracellular Signaling Peptides and Proteins Animal Models Chromatin Mitochondria Nucleic acids Chemistry Physical Sciences Epigenetics Cellular Structures and Organelles DNA modification Life Sciences & Biomedicine Chromatin modification Research Article Chromosome biology medicine.medical_specialty Human pancreatic-islets Carbohydrates Mouse Models Biology Bioenergetics Research and Analysis Methods 03 medical and health sciences Insulin resistance Model Organisms Internal medicine medicine Genetics Animals Humans DSCR1 Molecular Biology Ecology Evolution Behavior and Systematics Metaolism Diabetic Endocrinology Science & Technology Endocrine Physiology Protein Organic Chemistry Calcium-Binding Proteins Chemical Compounds Biology and Life Sciences Cell Biology DNA medicine.disease Aneuploidy Hormones Down-syndrome 030104 developmental biology Glucose Diabetes Mellitus Type 2 Gene Expression Regulation Oxidative stress Hyperglycemia Protein Biosynthesis Sydrome critical region Gene expression Down Syndrome Chromosome 21 030217 neurology & neurosurgery Genetic screen Model Developmental Biology |
| Zdroj: | Peiris, H; Duffield, MD; Fadista, J; Jessup, CF; Kashmir, V; Genders, AJ; et al.(2016). A Syntenic Cross Species Aneuploidy Genetic Screen Links RCAN1 Expression to β-Cell Mitochondrial Dysfunction in Type 2 Diabetes. PLoS Genetics, 12(5). doi: 10.1371/journal.pgen.1006033. UC Irvine: Retrieved from: http://www.escholarship.org/uc/item/69g1d108 Peiris, H, Duffield, M D, Fadista, J, Jessup, C F, Kashmir, V, Genders, A J, McGee, S L, Martin, A M, Saiedi, M, Morton, N, Carter, R, Cousin, M A, Kokotos, A, Oskolkov, N, Volkov, P, Hough, T A, Fisher, E M C, Tybulewicz, V L J, Busciglio, J, Coskun, P E, Becker, A, Belichenko, P V, Mobley, W C, Ryan, M T, Chan, J Y, Laybutt, D R, Coates, P T, Yang, S, Ling, C, Groop, L, Pritchard, M A & Keating, D J 2016, ' A syntenic cross species aneuploidy genetic screen links RCAN1 expression to β-cell mitochondrial dysfunction in Type 2 diabetes ', PLoS Genetics . https://doi.org/10.1371/journal.pgen.1006033 PLoS Genetics, Vol 12, Iss 5, p e1006033 (2016) PLoS Genetics |
| Popis: | Type 2 diabetes (T2D) is a complex metabolic disease associated with obesity, insulin resistance and hypoinsulinemia due to pancreatic β-cell dysfunction. Reduced mitochondrial function is thought to be central to β-cell dysfunction. Mitochondrial dysfunction and reduced insulin secretion are also observed in β-cells of humans with the most common human genetic disorder, Down syndrome (DS, Trisomy 21). To identify regions of chromosome 21 that may be associated with perturbed glucose homeostasis we profiled the glycaemic status of different DS mouse models. The Ts65Dn and Dp16 DS mouse lines were hyperglycemic, while Tc1 and Ts1Rhr mice were not, providing us with a region of chromosome 21 containing genes that cause hyperglycemia. We then examined whether any of these genes were upregulated in a set of ~5,000 gene expression changes we had identified in a large gene expression analysis of human T2D β-cells. This approach produced a single gene, RCAN1, as a candidate gene linking hyperglycemia and functional changes in T2D β-cells. Further investigations demonstrated that RCAN1 methylation is reduced in human T2D islets at multiple sites, correlating with increased expression. RCAN1 protein expression was also increased in db/db mouse islets and in human and mouse islets exposed to high glucose. Mice overexpressing RCAN1 had reduced in vivo glucose-stimulated insulin secretion and their β-cells displayed mitochondrial dysfunction including hyperpolarised membrane potential, reduced oxidative phosphorylation and low ATP production. This lack of β-cell ATP had functional consequences by negatively affecting both glucose-stimulated membrane depolarisation and ATP-dependent insulin granule exocytosis. Thus, from amongst the myriad of gene expression changes occurring in T2D β-cells where we had little knowledge of which changes cause β-cell dysfunction, we applied a trisomy 21 screening approach which linked RCAN1 to β-cell mitochondrial dysfunction in T2D. Author Summary Mitochondrial dysfunction and reduced insulin secretion are key features of β-cell dysfunction in Type 2 diabetes (T2D). Down syndrome (DS) is a genetic disorder caused by trisomy of chromosome 21 that also displays β-cell mitochondrial dysfunction and reduced insulin secretion in humans. Given these similarities in β-cell dysfunction in T2D and DS, we developed a trisomy 21 screening method to identify genes that may be important in T2D. This approach used different DS mouse models combined with human gene expression data from T2D β-cells. From this we identified a single candidate, Regulator of calcineurin 1 (RCAN1). High RCAN1 expression occurs in human and mouse T2D islets. Increased RCAN1 expression in mice reduced β-cell mitochondrial function and ATP availability, and this has negative implications for multiple ATP-dependent steps in glucose-stimulated insulin secretion. |
| Databáze: | OpenAIRE |
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