SFB 1309: Chemical Biology of Epigenetic Modifications

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Biomolecules that are produced in cells by DNA replication, RNA transcription and protein translation are often chemically modified. DNA contains modified nucleosides in order to increase the diversity of the genetic code, which is needed to switch parts of the genetic system between active and passive. RNA contains non-canonical nucleosides to introduce functions beyond information encoding. The modifications are needed to fine tune the decoding process and to stabilize specific RNA folds. Proteins in turn are post-synthetically modified in order to modulate their interaction with other proteins, with nucleic acids, to regulate their distribution in the cell and to stir their stability. The chemical language on all biomolecules establishes a new epigenetic layer of information that is not encoded by the DNA sequence. The CRC 1309 has the overarching goal to decode this information layer. Our aims are to investigate and manipulate the structure of the modification layers. In area A we are studying modifications on DNA and RNA. In area B the modification chemistry on proteins is in the focus. Finally, in area C the CRC 1309 develops new technologies to study this new information layer. New sequencing methods are developed to decipher, where modified nucleosides are situated in the genome or transcriptome. New mass spectrometry tools are required to investigate the content and dynamics of protein and nucleic acid modifications. The CRC 1309 uses the technologies of Chemical Biology to approach these goals. The modified nucleosides are chemically synthesized by modern solution phase chemistry. Solid phase chemistry methods are employed to prepare specifically modified DNA and RNA. These chemical tools are combined with Cell Biology to understand the function of the modification chemistry in vivo. In order to enable manipulation of the epigenetic information layer, molecules are developed that function as specific inhibitors for the enzymes that perform the modification chemistry. These compounds open new doors for the treatment of diseases. The new analytical methods allow us to study the distribution of modified amino acids in proteins and nucleosides in the biosphere. They lead the way to new cancer diagnostic tools. Using modern Cell Biology, we unravel how these non-canonical building blocks of proteins and oligonucleotides allow higher multicellular organisms to orchestrate transcriptional activity, particularly during cellular development and neuronal differentiation. Finally, we study how the modification chemistry evolved. Are for example non-canonical nucleosides relics of an early RNA world, or are they late developments that were needed to allow life to move to a higher level of complexity? The overarching goal of the CRC 1309 is to understand the chemical language on biomolecules and to develop molecules to manipulate this information layer in order set the ground for new medical intervention possibilities.