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Genomic Gastroenterology - Previous and Current Research

For instance, our group has identified the first common risk factor for gallstone disease (ABCG5/8) through a genome-wide association study. This is now the most widely replicated human susceptibility gene for gallstone disease, which has been shown to confer an approximately twofold increase in gallstone risk. This gene codes for a heterodimeric biliary cholesterol transporter. In order to better understand the mechanistic disease effect conferred by ABCG5/8, genetic fine mapping and cellular assays established cholesterol hypersecretion caused by ABCG8-Asp19His amino acid change as the disease causing mechanisms in this disorder. Recently, our group lead the first genome-wide association study in alcoholic liver cirrhosis and identified variants in the MBOAT7 and TM6SF2 genes as new risk loci.

 

EPIGENETICS OF GI DISORDERS

Epigenetics describes heritable changes in gene expression without changing the DNA-sequence. To date three mechanisms are known to induce epigenetic changes: DNA methylation, histone modification and ncRNA associated gene silencing.

In our group, we focus on changes in DNA methylation in fatty liver disease where we were able to identify NAFLD-specific expression and methylation differences for nine genes coding for key enzymes in intermediate metabolism and insulin/insulin-like signaling. Intra-individual comparison of liver biopsies before and after bariatric surgery showed NAFLD-associated methylation changes to be partially reversible. Postbariatric and NAFLD-specific methylation signatures were clearly distinct both in gene ontology and transcription factor binding site analyses.

We extended the analysis by use of laser capture microdissection to get spatial information on DNA methylation and expression genes changes of disease genes in human liver samples. With this approach approach, we generated the first comprehensive positional catalogue of molecular signatures across liver zones of healthy and steatotic (up to early NASH) individuals.

 

DYSREGULATION OF TRANSLATION IN COMPLEX DISEASES

Eukaryotic protein synthesis involves three stages, initiation, elongation and termination, in which initiation is the rate-limiting step. The complex nature and the number of different factors involved in the translation initiation process harbours several mechanisms how protein synthesis can be controlled. These mechanisms can be divided in to two broad categories:

Global up- or downregulation of protein synthesis by changing the phosphorylation state or degradation of initiation factors and regulation of individual transcripts through the activity of cis-acting elements, like internal ribosomal entry sites (IRES), sequence specific RNA binding proteins, secondary structures influencing scanning kinetics, miRNAs and upstream open reading frames.

We use ribosomal profiling, a method which allows a transcriptome-wide mapping of ribosomes with sub-codon resolution to analyze the complex nature of translational dysregulation in metabolic diseases i.e. non-alcoholic fatty liver disease and different cancer entities.

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