News Article

DNA “control error” increases risk of diabetes

Neuherberg, 17 January 2014. Why do some people get cancer, while others do not? Who is susceptible to type 2 diabetes? Many diseases are closely associated with our DNA, and certain DNA markers indicate an increased risk of developing a disease such as breast cancer. In most cases, however, it is not clear which DNA variants will actually trigger a disease – and in which way. Thanks to a new process, scientists have now succeeded in identifying a variant that plays a direct role in the onset of type 2 diabetes. Their findings are published in the current issue of Cell.

A DNA “control error” increases the risk of type 2 diabetes. This knowledge is based on a new process which has enabled researchers to compare DNA sequences in different species. (Source: Michael Pütz Design Print)
A DNA “control error” increases the risk of type 2 diabetes. This knowledge is based on a new process which has enabled researchers to compare DNA sequences in different species. (Source: Michael Pütz Design Print)


A number of institutes were involved in the study, including the Technical University of Munich (TUM), the Helmholtz Zentrum München, Harvard Medical School in Boston, USA, the University of Bergen, Norway, Genomatix Software GmbH, Germany, and Weill Cornell Medical College in Qatar.  

Scientists around the world are conducting research into the human DNA code in order to gain a better understanding of the part it plays in disease – with the aim of developing new therapies. However, the genes that contain the blueprint for all proteins account for only about 1 percent of DNA. The remaining 99 percent is not translated into proteins and is therefore classified as non-coding DNA.  
 
“We know that diseases are often associated with non-coding DNA regions,” explains Dr. Melina Claussnitzer from the Else Kröner-Fresenius Center for Nutritional Science at TUM. “These sequences evidently control whether a protein is coded and how much protein is formed. Diseases can therefore be caused by errors in DNA regulation.”

For the first time, the scientists identified a DNA “control error” as a trigger for type 2 diabetes. “Before a gene can be selected and translated into a protein, it must first be activated,” notes Prof. Hans Hauner, who heads the working group at the Technical University in Munich (TUM) and the clinical collaboration team exploring the interaction between nutrition and genetics in type 2 diabetes in cooperation with the Helmholtz Zentrum München. “Proteins give the starting signal. These so-called transcription factors then bind to certain non-coding DNA regions.”

The newly discovered type 2 diabetes variant interferes with the interaction between the DNA binding site and the transcription factors. “Ultimately that means that not enough glycerol 3-phospate, which plays a key role in fat metabolism, is produced. This results in a higher concentration of free fatty acids, which are considered to be a risk factor for insulin resistance, a precursor of type 2 diabetes,” Dr. Claussnitzer says.

For their investigations into non-coding DNA regions, the scientists developed a new computer-aided process that compares the DNA binding sites of different vertebrate species. The researchers were particularly interested in recurring patterns in these sites.

This method is based on the fact that important DNA sequences have persisted throughout evolution across different species. The more similar the sequences, the greater their biological significance. This enables scientists to track down key DNA binding sites and their variants.

PCMA (Phylogenetic Module Complexity Analysis) can be applied to different diseases such as osteoporosis, Alzheimer’s or cancer, in addition to type 2 diabetes. It thus opens up new possibilities in the identification of disease risks associated with non-coding DNA.  


Further Information

Original publication:
Leveraging Cross-Species Transcription Factor Binding Site Patterns: From Diabetes Risk Loci to Disease Mechanisms; Melina Claussnitzer, Simon N. Dankel, Bernward Klocke, Harald Grallert, Viktoria Glunk, Tea Berulava, Heekyoung Lee, Nikolay Oskolkov, Joao Fadista, Kerstin Ehlers, Simone Wahl, Christoph Hoffmann, Kun Qian, Tina Ronn, Helene Riess, Martina Müller-Nurasyid, Nancy Bretschneider, Timm Schroeder, Thomas Skurk, Bernhard Horsthemke, DIAGRAM+Consortium, Derek Spieler, Martin Klingenspor, Martin Seifert, Michael J. Kern, Niklas Mejhert, Ingrid Dahlman, Ola Hansson, Stefanie M. Hauck, Matthias Blüher, Peter Arner, Leif Groop, Thomas Illig, Karsten Suhre, Yi-Hsiang Hsu, Gunnar Mellgren, Hans Hauner, and Helmut Laumen, Cell (2014),


Link to publication


The Helmholtz Zentrum München, the German Research Center for Environmental Health, pursues the goal of developing personalized medicine, i.e. a customized approach to the diagnosis, treatment and prevention of widespread diseases such as diabetes mellitus and lung disease. To that end, it investigates the interaction of genetics, environmental factors and lifestyle. The Helmholtz Zentrum München is headquartered in Neuherberg in the north of Munich. It has about 2,200 staff members and is a member of the Helmholtz Association, Germany’s largest scientific organization, a community of 18 scientific-technical and medical-biological research centers with some 34,000 staff members. The Helmholtz Zentrum München is a partner in the German Center for Diabetes Research.



Contact
Technische Universität München
Else Kröner-Fresenius-Zentrum für Ernährungsmedizin



Specialist Contact

Melina Claussnitzer (Harvard Medical School, Boston, USA)
Tel. + 001 617 852-1948
melinaclaussnitzer(at)hsl.harvard.edu
melina.claussnitzer(at)tum.de

Prof. Dr. Hans Hauner
Tel. +49 8161 71-2000


Dr. Helmut Laumen
Tel. +49 8161 71-2006