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Prof. Dirk Schwarzer “Chemical tools for chromatin-modifying enzymes”
May 30, 2017 @ 4:30 pm
Chemical tools for chromatin-modifying enzymes
Prof. Dirk Schwarzer
Interfaculty Institute of Biochemistry, University of Tübingen
Chromatin is the universal template of genetic information in all eukaryotic organisms. Chemical modifications of the DNA-packaging histone proteins are crucial signaling events directing the use and readout of eukaryotic genomes. The enzymes that install and remove these chromatin modifications as well as the proteins that bind these marks govern information that goes beyond the sequence of DNA. Histone deacetylases (HDACs) interact with chromatin and erase acetylation marks of lysine residues in histones and non-histone proteins and thereby modulate the function and activity of these proteins. Alterations in histone acetylation levels and HDAC activity are transformations that occur in a wide range of diseases and consequently HDACs have been established as promising drug targets.
We have developed a chemical tool-set for probing histone modifications and HDAC activity. The interaction profiles of the endogenous human HDAC complexes were studied with different sets of probes, showing how substrate recognition and composition of HDAC complexes is modulated by the sequence context of the acetylation sites. We further demonstrated that the interaction profiles reflect the catalytic activity of respective HDACs. These results underline the utility of chemical probes for deciphering activity, substrate selectivity and composition of chromatin-modifying enzymes, which can hardly be achieved otherwise.