Theranostics 2020; 10(2):797-815. doi:10.7150/thno.38483 This issue

Research Paper

Allosteric regulation of protein 14-3-3ζ scaffold by small-molecule editing modulates histone H3 post-translational modifications

Yan-Jun Wan1*, Li-Xi Liao1*, Yang Liu1*, Heng Yang1, Xiao-Min Song1, Li-Chao Wang1, Xiao-Wen Zhang1, Yi Qian1, Dan Liu2, Xiao-Meng Shi1, Li-Wen Han3, Qing Xia3, Ke-Chun Liu3, Zhi-Yong Du1, Yong Jiang1, Ming-Bo Zhao1, Ke-Wu Zeng1✉, Peng-Fei Tu1✉

1. State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
2. Proteomics Laboratory, Medical and Healthy Analytical Center, Peking University Health Science Center, Beijing 100191, China.
3. Biology Institute, Qilu University of Technology (Shandong Academy of Sciences), Jinan, Shandong 250103, China.
* These authors contributed equally to this work.

This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions.
Citation:
Wan YJ, Liao LX, Liu Y, Yang H, Song XM, Wang LC, Zhang XW, Qian Y, Liu D, Shi XM, Han LW, Xia Q, Liu KC, Du ZY, Jiang Y, Zhao MB, Zeng KW, Tu PF. Allosteric regulation of protein 14-3-3ζ scaffold by small-molecule editing modulates histone H3 post-translational modifications. Theranostics 2020; 10(2):797-815. doi:10.7150/thno.38483. Available from https://www.thno.org/v10p0797.htm

File import instruction

Abstract

Graphic abstract

Background: Histone post-translational modifications (PTMs) are involved in various biological processes such as transcriptional activation, chromosome packaging, and DNA repair. Previous studies mainly focused on PTMs by directly targeting histone-modifying enzymes such as HDACs and HATs.

Methods and Results: In this study, we discovered a previously unexplored regulation mechanism for histone PTMs by targeting transcription regulation factor 14-3-3ζ. Mechanistic studies revealed 14-3-3ζ dimerization as a key prerequisite, which could be dynamically induced via an allosteric effect. The selective inhibition of 14-3-3ζ dimer interaction with histone H3 modulated histone H3 PTMs by exposing specific modification sites including acetylation, trimethylation, and phosphorylation, and reprogrammed gene transcription profiles for autophagy-lysosome function and endoplasmic reticulum stress.

Conclusion: Our findings demonstrate the feasibility of editing histone PTM patterns by targeting transcription regulation factor 14-3-3ζ, and provide a distinctive PTM editing strategy which differs from current histone modification approaches.

Keywords: Histone post-translational modifications, 14-3-3ζ, allosteric effect, autophagy-lysosome function, endoplasmic reticulum stress