will take place on Tuesday, October 18, 2016 from 17:15 to 18:15 hours in CBBM Research Building, EG, Room 50/51.
Host: Prof. Dr. Hendrik Lehnert
Department of Internal Medicine I
Universität zu Lübeck
Abstract
Obesity is by far the most common nutritional disease worldwide with type 2 diabetes as the most important complication. Since 2007, genome-wide association studies (GWAS) have identified numerous susceptibility loci associated with obesity and type 2 diabetes (T2D) traits. The majority of genetic variants at common risk loci are located in non-coding regions, suggesting cis-regulatory variants modulating gene expression. However, the precise molecular mechanisms underlying the associations of these variants with disease risk remain elusive in most cases. To identify the potential “causal” variants within LD blocks we established a novel bioinformatics approach called PMCA (phylogenetic module complexity analysis) which exploits the conservation of transcription factor binding site patterns across species (Claussnitzer et al., Cell 2014). In combination with novel epigenomic tools (e.g. from the ROADMAP Project) and genome editing (e.g. CRISPR/Cas9) we developed a novel integrative approach to dissect causality from GWAS data which also includes cellular and mouse models to identify the underlying pathomechanisms.
As a showcase we recently studied the association of a non-coding variant in the FTO locus with obesity. The strongest GWAS signal was located in a 47-kb region of the first 2 introns of the gene. This region contains 89 genetic variants in high LD. Using chromatin state annotation data a 12.8 kb-long enhancer was found in intron 1 that was most active in mesenchymal adipocyte progenitor cells. In an eQTL analysis, expression levels of IRX3 and IRX5 were higher in the carriers of the FTO risk haplotype compared with non-carriers. Using PMCA, the rs1421085 (T/C) variant in a conserved binding site was found to disrupt the binding of the ARID5B transcriptional repressor resulting in increased enhancer activity and subsequent increases in expression of the target genes IRX3 and IRX5. Genome editing experiments using CRISPR/Cas9 technology showed that C-to-T-editing increased catecholamine-induced oxygen consumption (Claussnitzer et al., NEJM 2015). Thereby, the dataset suggests that the ARID5B-FTO-IRX3-IRX5 pathway promotes the browning of adipocytes and increases thermogenesis offering potential new targets for drug development to treat obesity.
Further experiments were focusing on the physiological consequences in humans. Analysis of data on basal metabolic rate from a large cohort did not reveal an association with the risk genotype. Studies on genotype-dependent energy expenditure in humans under cold exposure are ongoing. Targeted metabolomics did not reveal differences in plasma metabolites between carriers and non-non-carriers of the risk genotype, however, efforts to search for circulating biomarkers of “browning” are currently extended.
In conclusion, the combination of novel state-of-the-art technologies may allow a systematic translational search to gain mechanistic insights into genetic associations with common human diseases.
Biosketch
Since 2003, Prof. Hauner has been Director of the Else Kröner Fresenius Center for Nutritional Medicine, with locations at TUM’s Klinikum Rechts der Isar and the Weihenstephan Center of Life and Food Sciences. His research explores diet-related chronic diseases such as obesity and type 2 diabetes. He also focuses on nutrition during pregnancy and fetal programming, functional genomics of risk genes for obesity and type 2 diabetes and the development of new nutrition concepts.
Prof. Hauner studied medicine at the University of Regensburg and TUM. Following his postdoctoral training at the University of Regensburg’s Department of Biochemistry, Microbiology and Genetics, he did the specialist training at the University of Ulm, specializing in endocrinology/diabetology. After that, he became senior consultant and deputy head of the Clinical Department of the German Diabetes Center at Heinrich-Heine University Düsseldorf. In 2003, he accepted the newly-created Chair of Nutritional Medicine at TUM. Prof. Hauner has been a member of the German Academy of Sciences (Leopoldina) since 2003 and is the spokesman for the German Federal Ministry of Education and Research’s “Adipositas” diabetes competence network since 2008.
