Proteomics helps to understand the influence of genetic variations
How does type 2 diabetes develop? A team of researchers headed by the Helmholtz Zentrum München and the Technical University of Munich has come closer to finding an answer to this problem. The team examined the functional effects of exemplary genetic variations relevant for type 2 diabetes. Their approach can be applied to many clinical pictures.
The risk of complex diseases such as type 2 diabetes increases by changes in our genetic makeup — our DNA. One contributing factor in the development of diseases are single nucleotide polymorphisms (SNP), which scientists call 'snips' for short. SNPs are variations of a single base pair occuring in a DNA molecule, but the modulated mechanisms remain elusive in most cases.
It is known that some of these risk SNPs influence the regulation of genes. Furthermore, it is also known that special proteins control gene regulation. Risk SNPs probably influence how these proteins or protein complexes bind to DNA. "So far scientists have only rarely succeeded in detecting a differential binding of gene-regulating protein complexes at disease-specific SNPs," explained Dr Helmut Laumen of the Clinical Cooperation Group (CCG) Nutrigenomics and Type 2 Diabetes and the Department of Pediatric Nutritional Medicine at the Technical University of Munich. The CCG is a cooperation project between the Helmholtz Zentrum München (Institute for Epidemiology 2) and the Technical University of Munich (Else Kröner-Fresenius Center for Nutritional Medicine, EKFZ).
"It would be particularly interesting to learn more about the different involved proteins that have a strong influence on gene regulation," said Laumen. A team from the Helmholtz Zentrum München and TUM performed a closer analysis of these mechanisms influenced by SNPs and published a study on the topic in Nucleic Acids Research.
Gap closed between genetic variations and an understanding of their function
The team has successfully used highly sensitive mass spectrometric methods to identify previously unknown proteins and protein complexes, whose binding to DNA is influenced by SNPs. "Here we could close the gaps that exist today between genetic variations and an understanding of their functional effect on the organism," explained Dr Stefanie Hauck, head of the Research Unit Protein Science and Core Facility Proteomics at the Helmholtz Zentrum München.
"Concretely, we apply these methods to SNPs that are relevant to type 2 diabetes and to age-related macular degeneration (AMD)," said Hauck. "In the future, the method will make it possible to identify functionally relevant proteins for all disease-associated SNPs, in order to uncover the mechanisms behind a clinical picture." An exact understanding of the molecular mechanisms that are modulated by regulatory SNPs can contribute to further development of personalized medicine.
Participating in the work were the Protein Science Research Unit and Proteomics Core Facility (Helmholtz Zentrum München), the Nutrigenomics and Type 2 Diabetes Clinical Cooperation Group (Helmholtz Zentrum München, Technical University of Munich) and the Else Kröner-Fresenius-Center for Nutritional Medicine (Technical University of Munich, Clinical Nutritional Medicine, Paediatric Nutritional Medicine).
Publication: Allele-specific quantitative proteomics unravels molecular mechanisms modulated by cis-regulatory PPARG locus variation. Nucleic Acids Research, DOI: 10.1093/nar/gkx105 Verlinken mit: https://doi.org/10.1093/nar/gkx105
Technical University of Munich
Chair for Paediatric Nutritional Medicine
Dr. Helmut Laumen
Mail: [email protected]
Helmholtz Zentrum München
Research Unit Protein Science
Dr. Stefanie Hauck
Mail: [email protected]
Technical University of Munich (TUM) is one of Europe's leading research universities, with more than 500 professors, around 10,000 academic and non-academic staff, and 40,000 students. Its focus areas are the engineering sciences, natural sciences, life sciences and medicine, combined with economic and social sciences. TUM acts as an entrepreneurial university that promotes talents and creates value for society. In that it profits from having strong partners in science and industry. It is represented worldwide with a campus in Singapore as well as offices in Beijing, Brussels, Cairo, Mumbai, San Francisco, and São Paulo. Nobel Prize winners and inventors such as Rudolf Diesel, Carl von Linde, and Rudolf Mößbauer have done research at TUM. In 2006 and 2012 it won recognition as a German "Excellence University." In international rankings, TUM regularly places among the best universities in Germany.
The Helmholtz Zentrum München, as the German Research Center for Environmental Health, pursues the objective of developing personalized medicine for the diagnosis, therapy and prevention of widespread diseases such as diabetes mellitus and lung diseases. To this end, it investigates the interactions of genetics, environmental factors and lifestyle. The Zentrum's headquarters is located in Neuherberg in the north of Munich. The Helmholtz Zentrum München employs around 2,300 people and is a member of the Helmholtz Association, which has 18 scientific-technical and biological-medical research centres with around 37,000 employees.
Dr. Helmut Laumen