A Live-Cell Epigenome Manipulation by Photo-stimuli-responsive Histone Methyltransferase Inhibitor

Post-translational modifications (PTMs) on the histone H3 tail regulate chromatin structure and impact epigenetics and hence the gene expressions. Current chemical modulation tools, such as unnatural amino acid incorporation, protein splicing, and sortase-based editing, have allowed for the modification of histones with various PTMs in cellular contexts, but most of these methods are not applicable for editing native chromatin. The use of small organic molecules to manipulate histone-modifying enzymes alters endogenous histone PTMs but lacks precise temporal and spatial control. To date, there has been no achievement in modulating biologically significant histone methylation in living cells with spatiotemporal resolution. In this study, we present a new method for temporally editing dimethylation H3K9me2 using a photo-responsive inhibitor that specifically targets the histone methyltransferase G9a upon light irradiation. The photo-caged molecule was stable under physiological conditions and in cellular environments, but rapidly decomposed upon exposure to light, releasing the bioactive component that can immediately inhibit the catalytic ability of the G9a in vitro. Besides, this masked compound could also efficiently promote the inhibition of methyltransferase activity in living cells, subsequently suppress H3K9me2, a mark that regulates various chromatin functions. Therefore, our chemical system will be a valuable tool for manipulating the epigenome for therapeutic purposes and furthering the understanding of epigenetic mechanisms.