Development of nucleus-targeted histone-tail-based photoaffinity probes to profile the epigenetic interactome in native cells

Yu Wang, Jian Fan, Xianbin Meng, Qingyao Shu, Yincui Wu, Guo-Chao Chu (), Rong Ji, Yinshan Ye, Xiangwei Wu, Jing Shi, Haiteng Deng, Lei Liu () and Yi-Ming Li ()
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Yu Wang: Hefei University of Technology
Jian Fan: University of Science and Technology of China
Xianbin Meng: Tsinghua University
Qingyao Shu: University of Science and Technology of China
Yincui Wu: Hefei University of Technology
Guo-Chao Chu: Tsinghua University
Rong Ji: Hefei University of Technology
Yinshan Ye: Hefei University of Technology
Xiangwei Wu: Tsinghua University
Jing Shi: University of Science and Technology of China
Haiteng Deng: Tsinghua University
Lei Liu: Tsinghua University
Yi-Ming Li: Hefei University of Technology

Nature Communications, 2025, vol. 16, issue 1, 1-13

Abstract: Abstract Dissection of the physiological interactomes of histone post-translational modifications (hPTMs) is crucial for understanding epigenetic regulatory pathways. Peptide- or protein-based histone photoaffinity tools expanded the ability to probe the epigenetic interactome, but in situ profiling in native cells remains challenging. Here, we develop a nucleus-targeting histone-tail-based photoaffinity probe capable of profiling the hPTM-mediated interactomes in native cells, by integrating cell-permeable and nuclear localization peptide modules into an hPTM peptide equipped with a photoreactive moiety. These types of probes, such as histone H3 lysine 4 trimethylation and histone H3 Lysine 9 crotonylation probes, enable the probing of epigenetic interactomes both in HeLa cell and hard-to-transfect RAW264.7 cells, resulting in the discovery of distinct interactors in different cell lines. The utility of this probe is further exemplified by characterizing interactome of emerging hPTM, such as AF9 was detected as a binder of histone H3 Lysine 9 lactylation, thus expanding the toolbox for profiling of hPTM-mediated PPIs in live cells.

Date: 2025
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DOI: 10.1038/s41467-024-55046-8

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