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A Mystery Solved: How Genes Are Selectively Silenced

No. 55 | 18/10/2010 | by Koh

Cells have to use their resources economically. Therefore, they read only those genes which are needed at a given moment, while the others are chemically labeled and, thus, selectively turned off. Scientists at the German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ) have now been the first to discover how these labels are placed at exactly the right spot in the genetic material. Important players are regulatory RNA molecules. Their sequence exactly matches the region of a gene which is to be labeled. At this site, RNA and DNA form a plait-like triple helix serving as a signpost for the labels.

enlarged view © dkfz.de

Our genetic material is often compared to a book. However, it is not so much like a novel to be read in one piece, but rather like a cookbook. The cell reads only those recipes which are to be cooked at the moment. The recipes are the genes; 'reading' in the book of the cell means creating RNA copies of individual genes, which will then be translated into proteins.

The cell uses highly complex, sophisticated regulatory mechanisms to make sure that not all genes are read at the same time. Particular gene switches need to be activated and, in addition, there are particular chemical labels in the DNA determining which genes are transcribed into RNA and which others will be inaccessible, i.e. where the book literally remains closed. The biological term for this is epigenetic gene regulation.

Among the epigenetic mechanisms which are well studied is the silencing of genes by methyl groups. This is done by specialized enzymes called methyltransferases which attach methyl labels to particular 'letters' of a gene whereby access to the whole gene is blocked. "One of the great mysteries of modern molecular biology is: How do methyltransferases know where to attach their labels in order to selectively inactivate an individual gene?" says Professor Ingrid Grummt of the German Cancer Research Center (DKFZ).

Grummt has now come much closer towards unraveling this mystery. She has focused on studying those text passages in the genetic material which do not contain any recipes. Nevertheless, these texts are transcribed into RNA molecules in a controlled manner. "These so-called noncoding RNAs do not contain recipes for proteins. They are important regulators in the cell which we are just beginning to understand," says Ingrid Grummt.

In her most recent work, Grummt and her co-workers have shown for the first time that epigenetic regulation and regulation by noncoding RNAs interact. The scientists artificially introduced a noncoding RNA molecule called pRNA into cells. As a result, methyl labels are attached to a particular gene switch so that the genes behind it are not read. The trick is that pRNA exactly matches (is complementary to) the DNA sequence of this gene switch. The investigators found out that pRNA forms a kind of plait, or triple helix, with the two DNA strands in the area of this gene switch. Methyltransferases, in turn, are able to specifically dock to this 'plait' and are thus directed exactly to the place where a gene is to be blocked.

More than half of our genetic material is transcribed into noncoding RNA. This prompts Ingrid Grummt to speculate: "It is very well possible that there are exactly matching noncoding RNA molecules for all genes that are temporarily silenced. This would explain how such a large number of genes can be selectively turned on and off."

Kerstin-Maike Schmitz, Christine Mayer, Anna Postepska and Ingrid Grummt: Interaction of noncoding RNA with the rDNA promoter mediates recruitment of DNMT3b and silencing of rRNA genes. Genes & Development 2010, DOI: 10.1101/gad.590910

The German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ) with its more than 3,000 employees is the largest biomedical research institute in Germany. At DKFZ, more than 1,000 scientists investigate how cancer develops, identify cancer risk factors and endeavor to find new strategies to prevent people from getting cancer. They develop novel approaches to make tumor diagnosis more precise and treatment of cancer patients more successful. The staff of the Cancer Information Service (KID) offers information about the widespread disease of cancer for patients, their families, and the general public. Jointly with Heidelberg University Hospital, DKFZ has established the National Center for Tumor Diseases (NCT) Heidelberg, where promising approaches from cancer research are translated into the clinic. In the German Consortium for Translational Cancer Research (DKTK), one of six German Centers for Health Research, DKFZ maintains translational centers at seven university partnering sites. Combining excellent university hospitals with high-profile research at a Helmholtz Center is an important contribution to improving the chances of cancer patients. DKFZ is a member of the Helmholtz Association of National Research Centers, with ninety percent of its funding coming from the German Federal Ministry of Education and Research and the remaining ten percent from the State of Baden-Württemberg.

last update: 18/10/2010 back to top