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