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Gene regulation

Reading the genetic code 2.0

Munich, 02/28/2013

The base sequences of our genes code for proteins, but which genes are expressed in any given cell is partly determined by chemical modifications of these bases. A new study reveals how proteins read and rewrite this “epigenetic” code.

The biological characteristics of all organisms are determined by the order of the chemical bases in their genes, which specifies the kind of protein synthesized in their cells in accordance with the genetic code. Four types of bases are found in all genomic DNAs – adenine, guanine, thymine and cytosine. Moreover, generally speaking, all the cells in an individual contain the same complement of genetic information. So cells also need a second layer of information that controls which genes are active at any time. This “epigenetic” code enables different cell types to express the genes that are essential for their specialized functions.

Researchers led by Professor Thomas Carell at the Department of Chemistry at LMU Munich, in collaboration with Professor Michiel Vermeulen’s group at Utrecht University in the Netherlands, now provide new insights into how this second level of genetic regulation operates. The epigenetic code makes use of four chemically modified bases, 5-methylcytosine (mC), and three oxidized derivatives of mC that have only been discovered in recent years – hydroxymethylcytosine (hmC), 5’-formylcytosine (fC), which was identified by Carell’s team in 2011, and 5’-carboxycytosine (caC).

Methylation of DNA – the attachment of CH3 groups to specific bases – is associated with gene repression. Thus, genes containing methylated cytosines display low levels of activity. However, the function of the other cytosine derivatives has remained obscure. In a cooperative effort together with LMU biologist Professor Heinrich Leonhardt, the researchers have used state-of-the-art analytical techniques to identify proteins that specifically recognize modified cytosines in stem cells, neural precursors and differentiated nerve cells in the mouse. The results identify the protein "readers" of the biological functions of the various modifications.

The study showed that the newly identified bases interact with a clearly defined set of proteins. Moreover, these proteins exhibit relatively little overlap in binding specificity, implying that each oxidized derivative has a defined function. Prominent among the proteins recruited are certain regulators of gene transcription, but also many DNA repair proteins. “The DNA repair proteins recognize fC and caC, and excise them from the DNA; they are then replaced by unmethylated cytosine. So DNA repair mechanisms also appear to play a role in gene activation,” says Carell.

The authors of the new study believe that the modified bases may act as switches during the the development of embryonic stem cells into mature differentiated cells with specialized functions in the adult organism. They also make it possible for genes to alternate between active and inactive phases. This is especially important for differentiated nerve cells, which can no longer divide, but must retain the capacity to respond to environmental influences. Hence, the identification of the proteins that read and rewrite the messages encoded by modified bases is of great significance for our understanding of cell function. (Cell 2013) göd

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