Live-Cell Epigenome Manipulation by Synthetic Histone Acetylation Catalyst System
Live-cell epigenome manipulation by synthetic histone acetylation catalyst system Yusuke Fujiwaraa, Yuki Yamanashia, Akiko Fujimuraa, Yuko Satob, Tomoya Kujiraic, Hitoshi Kurumizakac, Hiroshi Kimurab, Kenzo Yamatsugua,1, Shigehiro A. Kawashimaa,1, and Motomu Kanaia,1 aGraduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo 113-0033, Japan; bCell Biology Center, Institute of Innovative Research, Tokyo Institute of Technology, Yokohama 226-8503, Japan; and cInstitute for Quantitative Biosciences, The University of Tokyo, Tokyo 113-0033, Japan Edited by Tom W. Muir, Princeton University, Princeton, NJ, and accepted by Editorial Board Member Karolin Luger December 5, 2020 (received for review September 16, 2020) Chemical modifications of histones, such as lysine acetylation and lysine residues on histone tails. Interestingly, synthetic histone ubiquitination, play pivotal roles in epigenetic regulation of gene acetylation of Xenopus chromatin by 16DMAP with PAc-gly pre- expression. Methods to alter the epigenome thus hold promise as vented DNA replication in cell-free Xenopus egg extract system, tools for elucidating epigenetic mechanisms and as therapeutics. providing a novel link between histone acetylation and cell cycle However, an entirely chemical method to introduce histone modifi- (12). However, oligoDMAP-based catalysts did not work in live cations in living cells without genetic manipulation is unprecedented. cells, probably due to inactivation of the catalytically active species Here, we developed a chemical catalyst, PEG-LANA-DSSMe 11, that (i.e., acetyl pyridinium ion) under highly reductive and nucleo- ’ binds with nucleosome s acidic patch and promotes regioselective, philic environment in cells (e.g., the presence of glutathione synthetic histone acetylation at H2BK120 in living cells.
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