Unlocking fundamental principles of chromatin signalling

The genomes of eukaryotic organisms are covered by histone proteins, which act as a signalling platform that forms an integral part of the regulation and protection of the genome. The signals consist of post-translational modifications on histones for which there are "writer" and "eraser" enzymes as well as reader proteins that specifically bind the marks. This project focuses on an enzyme called Clr4 that is at the heart the fission yeast heterochromatin system, a very informative model system for understanding the fundamental mechanisms of signalling on chromatin. Clr4 deposits the histone H3 lysine 9 methyl marks (H3K9me), which are required to establish silent epigenetic states that can be propagated from one generation to the next without changes in the underlying DNA sequence. Clr4 is part of a large protein family also found in plants and animals, the SUV39 enzymes, which deposit H3K9me marks in many different organisms. In mammals, these enzymes have been shown to be required for healthy development and their deregulation is associated with various cancers.
Recent work in our laboratory has revealed that ubiquitination on a residue close to H3K9, lysine 14, can stimulate the activity of Clr4 on H3K9 by more than 250-fold (Stirpe et al.). We have furthermore evidence that phosphorylation on Clr4 itself regulates the H3K9 methyltransferase activity.
This project is part of an international collaborative effort that leverages our expertise in high-resolution structural approaches including X-ray crystallography, NMR and cryo-EM to visualize and understand how these post-translational modifications control Clr4. We will investigate the molecular dynamics of the system by multinuclear NMR and single-molecule experiments. This rich understanding of Clr4's regulation will inform the principles that govern mammalian homologs and will thereby be key to driving efforts to develop therapeutic approaches.