A New Genetic Switching Element in Stem Cells
Thursday, 22 May 2014
Slight modifications in their genome sequences play a crucial role in the conversion of pluripotent stem cells into various differentiated cell types. A team at Ludwig-Maximilians-Universitaet (LMU) in Munich has now identified the factor responsible for one class of modification.
Professor Thomas Carell from the Department
of Chemistry at LMU.
This explains why such DNA modifications play a major role in the differentiation of stem cells.
“Several unusual nucleobases have been found in the genomes of stem cells, which are produced by targeted chemical modification of the known building blocks of DNA. These ‘atypical’ bases are thought to be important in determining what types of differentiated cells can be derived from a given stem cell line,” says Professor Thomas Carell from the Department of Chemistry at LMU.
All of the unconventional bases so far discovered are derived from the same standard base – cytosine. Furthermore, Carell and his team have shown in earlier work that so-called Tet enzymes are always involved in their synthesis.
Base oxidation regulates gene activity
In cooperation with colleagues at LMU, as well as researchers based in Berlin, Basel and Utrecht, Carell and his group have now shown, for the first time, that a standard base other than cytosine is also modified in embryonic stem cells of mice. Moreover, Tet is at work here too.
“During the development of specialized tissues from stem cells, enzymes belonging to the Tet family also oxidize the thymidine base, as we have now shown with the aid of highly sensitive analytical methods based on mass spectrometry. The product of the reaction, hydroxymethyluracil, was previously – and as it now turns out, erroneously – thought to be synthesized by a different pathway,” Carell explains.
The precise function of hydroxymethyluracil remains unclear. However, using an innovative method for the identification of factors capable of binding to and “reading” the chemical tags that characterize unconventional DNA bases, Carell and colleagues have shown that stem cells contain specific proteins that recognize hydroxymethyluracil, and could therefore contribute to the regulation of gene activity in these cells.
“We hope that these new insights will make it possible to modulate the differentiation of stem cells – causing them to generate cells of a particular type,” says Carell.
“It would be wonderful if we were one day able to generate whole organs starting from differentiated cells produced, on demand, by stem cell populations.”
Contact: Luise Dirscherl
Tet oxidizes thymine to 5-hydroxymethyluracil in mouse embryonic stem cell DNA
Toni Pfaffeneder, Fabio Spada, Mirko Wagner, Caterina Brandmayr, Silvia K Laube, David Eisen, Matthias Truss, Jessica Steinbacher, Benjamin Hackner, Olga Kotljarova, David Schuermann, Stylianos Michalakis, Olesea Kosmatchev, Stefan Schiesser, Barbara Steigenberger, Nada Raddaoui, Gengo Kashiwazaki, Udo Müller, Cornelia G Spruijt, Michiel Vermeulen, Heinrich Leonhardt, Primo Schär, Markus Müller & Thomas Carell
Nature Chemical Biology Published online 18 May 2014, doi:10.1038/nchembio.1532
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