Epigenetic and Environmental Regulations of Complex Phenotypes
Principal investigator :
Dominique Gauguier, Ph.D.
Research team :
Françoise Homo-Delarche, Sophie Calderari
This research, which addresses novel concepts in the etiology of disease susceptibility and resistance, will be carried out through genomic and physiological studies predominantly in rodent models, where environmental factors are carefully controlled, followed by translational studies in CMD patients. The project is embedded in international research programmes with the ultimate aims to bring new knowledge on the etiology of human multifactorial disorders. To test both the existence of gut microbiota differences between CMD models and controls and the impact of host genetic differences on microbiota, microbiome sequencing will be performed in rat models derived from strains showing susceptibility (Goto-Kakizaki –GK) or resistance (Brown Norway –BN) to CMD, as well as in mouse models of high fat diet induced obesity. In parallel, we will identify detailed patterns of parent-of-origin dependent gene expression in multiple organs that account for epigenetic mechanisms involved in the inheritance of complex disorders through investigations in rat and mouse models and translational studies in CMD patients. Genome-wide gene expression profiling in hybrids carrying CMD alleles originating from the paternal or maternal lineage will be performed in key organs involved in glucose regulation. The project will deliver new paradigms for understanding relationships between CMD genetic susceptibility and epigenetic mechanisms and gut microbiome populations, as well as deeper understanding of microbiome networks and epigenetic marks underlying altered metabolic regulations in obesity and diabetes.
The project investigates the causative roles of epigenetic and gut microbiome influences in the etiology of complex phenotypes, with a specific focus on risk factors for cardio-metabolic diseases (CMD), which associate obesity, diabetes and hypertension.
Dominique Gauguier is INSERM Director of Research at the Cordeliers Research Centre in Paris, where he leads a team working on various genetic and functional genomic aspects of insulin resistance in model systems. Until 2009 he was Professor of Mammalian Genetics and Wellcome Senior Research Fellow at the Wellcome Trust Centre for Human Genetics, University of Oxford, UK, that he joined in 1994 as a post-doctoral research fellow. His research addressed etiological aspects of various complex diseases through approaches combining physiological and genetic studies in rodent models. He has been involved in several European Research Consortia and was coordinator of an EC FP6 programme (FGENTCARD) focusing on the application of functional genomic technologies in humans and animal models to decipher the etiology of coronary artery disease. He is involved in a FP7 integrated project (EURATRANS). His main current research interests are in the genetic control of pathophysiological traits and molecular phenotypes of the metabolome and the transcriptome in rodent models of spontaneous or experimentally induced complex diseases. He demonstrated the genetic dissection of diabetes traits and the mapping of molecular phenotypes of the metabolome in experimental crosses, and carried out translational studies designed to test in human genetics candidate genes identified in rodent models. His current projects aim at developing integrated strategies to understand the genetic and epigenetic regulations of dynamic gene expression in the context of systems biology.
1. Rat Genome Sequencing and Mapping Consortium. From sequence to phenotype variation in the laboratory rat. Nature Genetics in press (2013)
2. The CARDIoGRAMplusC4D Consortium. Coronary artery disease risk loci identified in over 190,000 individuals implicate lipid metabolism and inflammation as key causal pathways. Nature Genetics 45:25-33 (2013)
3. The STAR consortium. SNP and haplotype mapping for genetic analysis in the rat. Nature Genetics 40:560-566 (2008)
4. Aitman T, Critser JK, Cuppen E, Dominiczak A, Fernandez XM, Flint J, Gauguier D, Geurts AM, Gould M, Harris PC, Holmdahl R, Hübner N, Izsvak Z, Jacob H, Kuramoto T, Kwitek AE, Marrone A, Mashimo T, Moreno-Quinn C, Mullins J, Mullins L, Olsson T, Riley L, Saar K, Serikawa T, Shull JD, Szpirer C, Twigger SN, Voigt B, Worley K. Progress and prospects in rat genetics: a community view. Nature Genetics 40:516-522 (2008)
5. Dumas ME, Wilder SP, Bihoreau MT, Barton RH, Fearnside JF, Argoud K, D’Amato L, Wallis RH, Blancher C, Keun HC, Baunsgaard D, Scott J, Grove Sidelmann U, Nicholson JK, Gauguier D. Direct quantitative trait locus mapping of mammalian metabolic phenotypes in diabetic and normoglycemic rat models. Nature Genetics 39(5):666-672 (2007)