Johannes Schödel

Graduate Research Prize Winners 2012 

schodel

I gained my first taste of research, when I conducted a medical thesis in the Institute of Biochemistry II at the University of Jena, Germany from 2000 to 2002, in parallel with my undergraduate medical studies in Jena, and Padova (Italy). In this thesis I investigated the role of P2-purinoceptors, which are receptors for extracellular nucleotides such as ATP or UTP, on lipid metabolism in adipose tissue.

After finishing my final examinations in 2003, I started my training as a physician in the Department of Cardiology at the University of Würzburg, Germany. I continued to be engaged in research during this time and simultaneously with my clinical work, explored the different functions of nitric oxide synthases in atherogenesis using different transgenic mouse models in a research programme funded by the Interdisciplinary Centre for Clinical Research.

I then moved to Erlangen, Germany and started working as a physician in the Department of Nephrology and Hypertension at the University of Erlangen-Nuremberg, with Professor Kai-Uwe Eckardt. In this position I was able to combine my training as a Nephrologist with further research experience. This work aimed to characterize the regulation and relevance of hypoxia-inducible transcription in the kidney, focusing on the pathophysiology of renal injury. The hypoxia inducible transcription factors (HIF) are key mediators of the hypoxic response. Degradation and activity of HIF is controlled by oxygen dependent prolyl and asparagyl hydroxylases. I characterized both in vitro and in vivo expression and regulation of these enzymes in mammalian kidneys.

This research stimulated my interest in oxygen sensing and HIF-biology in general. I was awarded a Wellcome Trust Clinical Dphil Fellowship to work on the characterisation of HIF-DNA-bindings site and the genome-wide hypoxic response at the Centre for Cellular and Molecular Physiology in Henry Wellcome Building for Molecular Physiology in Oxford. Together with my supervisors Dr David Mole and Prof Peter Ratcliffe, I used chromatin-immunoprecipitation of HIF-subunits coupled to next-generation sequencing to dissect the genetic and epigenetic features of HIF-binding.

We found approximately 500 HIF-DNA-binding sites in each of 786-O renal cancer cells and in MCF-7 breast cancer cells with approximately 35% shared between the two. Comparison with pan-genomic expression analyses showed that HIF was acting as an enhancer, but not a repressor of gene transcription. Correlation with expression analyses from renal tumours indicated that many HIF-binding genes were upregulated in renal cancer.

One promoter-distant HIF-binding site that was specific to renal cancer was identified at an intergenic locus on chromosome 11q13.3 that has been associated with renal cancer in Genome-Wide Association Studies (GWAS). Together with Ian Tomlinson’s group from the Wellcome Trust Centre of Human Genetics and Veronica Buckle from the Weatherall Institute of Molecular Medicine we performed detailed genetic and epigenetic analyses of this locus. The HIF-binding site was in high linkage disequilibrium with the disease associated SNP and had the epigenetic hallmarks of an enhancer. Analysis of pan-genomic expression analyses identified a flanking gene (the cell-cycle regulator CCND1) as highly HIF-regulated and we showed a physical association between the HIF-binding site and the CCND1 promoter. Furthermore, using a cell line heterozygous at this locus at this locus, we were able to show that the renal cancer-protective allele disrupted HIF-binding leading to an allelic imbalance in CCND1 expression. This work identifies a direct link between a renal cancer susceptibility locus, the VHL tumour suppressor, the HIF-transcriptional pathway and the cell-cycle regulator cyclin D1 and emphasises the importance of understanding regulatory regions of the genome when interpreting GWAS signals. For this work I was awarded the Carl-Ludwig-Young-Investigator Award of the German Society of Nephrology.

Presently, I am pursuing my clinical training in Nephrology at the University of Erlangen-Nuremberg and continue to be involved in further research projects aiming to uncover the roles of HIF in renal tubular physiology and to explore the therapeutic potential of the HIF-system in kidney injuries such as acute renal failure or chronic kidney disease.

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