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Environmental and epigenetic regulation of complex phenotypes

Results from genome-wide association studies have shed new light on the complex etiology of common human diseases. Even though numerous susceptibility loci have been identified, they only explain a small fraction of the inherited disease risk and the biological function of the underlying genes is often unknown. Epigenetic and environmental influences, as well as gene x environment interactions, are likely to play important roles in these diseases. In recent years, our research relied on technological developments in genetics and functional genomics to apply emerging concepts of systems biology in models of cardiometabolic diseases (CMD) (type 2 diabetes, essential hypertension, obesity, dyslipidemia) to identify disease susceptibility genes and characterise underlying functional networks and disease associated biomarkers. Modern functional genomic technologies (metabolomics, transcriptomics), statistical genetics, bioinformatics and genome sequence data have been used by the team to generate new hypotheses in relation to the function of genes and biomarkers associated with CMD susceptibility and resistance.

The central theme of our research is the study of molecular mechanisms associated with epigenetic regulations and gene x environment interactions underlying human multifactorial disorders through investigations models, and the characterization of relevant biological functions at the whole organism, organ and cellular levels. Our research, which addresses novel concepts in the etiology of disease susceptibility and resistance, is discovery driven and combines genomic and physiological studies in animal models, where environmental factors are carefully controlled, and in cellular systems followed by translational applications in humans. Ongoing projects focus on the causative roles of epigenetic and gut microbiome influences in the regulation of complex phenotypes, with a specific focus on risk factors for CMD. Microbiome sequencing and metabolomic studies (NMR and mass spectrometry) are performed to test the existence of changes in the architecture and function of gut microbiota in CMD models and in patients. In parallel, the existence of patterns of parent-of-origin dependent genome-wide gene expression is tested in multiple organs that account for epigenetic mechanisms involved in the inheritance of complex disorders through investigations in hybrids carrying CMD alleles originating from the paternal or maternal lineage.

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 team is actively involved in international research programmes
( www.euratrans.eu ; www.metacardis.eu)
and in the Institute of Cardiometabolism and Nutrition
( www.ican-institute.org ).

 Team Leader : Dominique GAUGUIER (Dr)

Team Members : Francoise HOMO-DELARCHE (Dr), Noémie PEAN (Dr).
Aurélie LE LAY (Eng).
François BRIAL (Post-Doc), Fatiha TABET (PhD).

Administration : Valérie RESVE

Contact details : 33 (0)1 44 27 71 56, Email: valerie.resve@crc.jussieu.fr

Selected Publications :

  • Atanur S, Garcia Diaz A, Maratou K, Sarkis A, Rotival M, Game L, Tschannen MR, Kaisaki PJ, Otto GW, Chun John Ma M, Keane TM, Hummel O, Saar K, Chen W, Guryev V, Gopalakrishnan K, Garrett MR, Joe B, Citterio L, Bianchi G, McBride M, Dominiczak A, Adams DJ, Serikawa T, Flicek P, Cuppen E, Hubner N, Petretto E, Gauguier D, Kwitek A, Jacob H, Aitman TJ. Genome sequencing reveals loci under artificial selection that underlie disease phenotypes in the laboratory rat. Cell 154(3):691-703 (2013)
  • Rat Genome Sequencing and Mapping Consortium. Combined sequence-based and genetic mapping analysis of complex traits in outbred rats. Nature Genetics 45(7):767-75 (2013)
    The STAR consortium. SNP and haplotype mapping for genetic analysis in the rat. Nature Genetics 40(5):560-566 (2008)
  • Woon PY, Kaisaki PJ, Braganca J, Bihoreau MT, Levy J, Farrall M, Gauguier D. Polymorphisms in aryl hydrocarbon receptor nuclear translocator-like (Arntl, Bmal1) are associated with Type 2 diabetes and hypertension. Proc. Natl. Acad. Sci. USA 104(36):14412-14417 (2007)
  • 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)

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Link to PubMed

 

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