Division of Epigenetics
Prof. Dr. Frank Lyko
Epigenetic mechanisms regulate the interpretation of genetic information. As such, epigenetics plays an important role in mediating phenotypic plasticity. Important examples include cellular differentiation, transformation and aging, which all involve profound alterations in phenotypic plasticity.
DNA methylation is the longest known and best-characterized epigenetic modification. In the human genome, approximately 20 million cytosine residues are methylated in the context of CG dinucleotides. Importantly, altered DNA methylation patterns represent one of the earliest and most consistent hallmarks of human cancers. Hypermethylation-induced silencing of tumor suppressor genes has been documented in all cancers and can be reversed by the use of DNA methyltransferase inhibitors. This allows fundamentally new approaches in the clinical management of cancer.
Our research activities focus on the characterization of DNA methylation patterns in various models of phenotypic plasticity ranging from human tissue aging to caste specification in honeybees. In addition, we are developing DNA methyltransferase inhibitors as novel anticancer drugs. Here, our activities range from computer modelling to molecular biomarker analysis in clinical trials. Lastly, we are also establishing a new research focus on cytosine RNA methylation to investigate the potential function of this modification in the context of epigenetic regulation.
The division will continue its focus on three major topics, the role of DNA methylation in phenotypic plasticity, the development of DNA methyltransferase inhibitors and the functional characterization of RNA methylation. For the analysis of DNA methylation patterns, we will place strong emphasis on the use of next-generation sequencing technologies to establish genome-wide methylation maps from various model systems. For the development of DNA methylation inhibitors, we will focus on the further development of the azacytidine scaffold and thoroughly investigate the extended mode of action of 5-azacytidine and its derivatives. For the functional characterization of RNA methylation, we will combine a detailed analysis of RNA methyltransferase knockout models with a comprehensive characterization of RNA cytosine methylation patterns by next-generation sequencing.
Raddatz, G., Gao, Q., Bender, S., Jaenisch, R., and Lyko, F. (2012). Dnmt3a protects active chromosome domains against cancer-associated hypomethylation. PLoS Genetics 8: e1003146.
Tuorto, F., Liebers, R., Musch, T., Schaefer, M., Hofmann, S., Kellner, S., Frye, M., Helm, M., Stoecklin, G., and Lyko, F. (2012). RNA cytosine methylation by Dnmt2 and NSun2 promotes tRNA stability and protein synthesis. Nature Struct. Mol. Biol. 19: 900-905.
Schaefer, M., Pollex, T., Hanna, K., Tuorto, F., Meusburger, M., Helm, M., and Lyko, F. (2010). RNA methylation by Dnmt2 protects transfer RNAs against stress-induced cleavage. Genes and Development 24: 1590-1595.
Lyko, F., Foret, S., Kucharski, R., Wolf, S., Falckenhayn, C., and Maleszka, R. (2010). The honey bee epigenomes: differential methylation of brain DNA in queens and workers. PLoS Biology 8: e1000506.