研究実績
2025
1.
Tamiko Nozaki, Mayu Onoda, Misuzu Habazaki, Yuma Takeuchi, Hisashi Ishida, Yuko Sato, Tomoya Kujirai, Kayo Hanada, Kenzo Yamatsugu, Hitoshi Kurumizaka, Hiroshi Kimura, Hidetoshi Kono, Shigehiro A. Kawashima, Motomu Kanai
Designer Catalyst-Enabled Regiodivergent Histone Acetylation Journal Article
In: J. Am. Chem. Soc., 2025, ISSN: 1520-5126.
Abstract | Links | タグ: Kawashima G, Kimura G, Kurumizaka G
@article{Nozaki2025,
title = {Designer Catalyst-Enabled Regiodivergent Histone Acetylation},
author = {Tamiko Nozaki and Mayu Onoda and Misuzu Habazaki and Yuma Takeuchi and Hisashi Ishida and Yuko Sato and Tomoya Kujirai and Kayo Hanada and Kenzo Yamatsugu and Hitoshi Kurumizaka and Hiroshi Kimura and Hidetoshi Kono and Shigehiro A. Kawashima and Motomu Kanai},
url = {https://pubs.acs.org/doi/full/10.1021/jacs.5c01699},
doi = {10.1021/jacs.5c01699},
issn = {1520-5126},
year = {2025},
date = {2025-04-13},
urldate = {2025-04-13},
journal = {J. Am. Chem. Soc.},
publisher = {American Chemical Society (ACS)},
abstract = {The “histone code,” defined by the combinatorial patterns of post-translational modifications (PTMs) on histones, plays a pivotal role in chromatin structure and gene expression. Tools for the regioselective introduction of histone PTMs in living cells are critical for dissecting the functions of these epigenetic marks. Here, we report the design and development of three regioselective catalysts that acetylate distinct lysine residues (K43, K108, and K120) on histone H2B. Using a combination of molecular dynamics simulations of catalyst-nucleosome complexes and systematic experimental optimization of catalyst structures, we identified key design principles for achieving regioselectivity. Specifically, excluding highly reactive off-target lysine residues from the catalyst effective region (CER) while maintaining proximity to a target lysine residue proved crucial. Biochemical and cellular analyses of the catalytic histone acetylation revealed that each lysine acetylation elicited unique effects on the binding affinity and activity of nucleosome-interacting molecules, as well as on transcriptional programs and cellular phenotypes. These findings establish a framework for designing regioselective histone acetylation catalysts and advance our understanding of the regulatory mechanisms underlying histone PTMs.},
keywords = {Kawashima G, Kimura G, Kurumizaka G},
pubstate = {published},
tppubtype = {article}
}
The “histone code,” defined by the combinatorial patterns of post-translational modifications (PTMs) on histones, plays a pivotal role in chromatin structure and gene expression. Tools for the regioselective introduction of histone PTMs in living cells are critical for dissecting the functions of these epigenetic marks. Here, we report the design and development of three regioselective catalysts that acetylate distinct lysine residues (K43, K108, and K120) on histone H2B. Using a combination of molecular dynamics simulations of catalyst-nucleosome complexes and systematic experimental optimization of catalyst structures, we identified key design principles for achieving regioselectivity. Specifically, excluding highly reactive off-target lysine residues from the catalyst effective region (CER) while maintaining proximity to a target lysine residue proved crucial. Biochemical and cellular analyses of the catalytic histone acetylation revealed that each lysine acetylation elicited unique effects on the binding affinity and activity of nucleosome-interacting molecules, as well as on transcriptional programs and cellular phenotypes. These findings establish a framework for designing regioselective histone acetylation catalysts and advance our understanding of the regulatory mechanisms underlying histone PTMs.
