Dataset Information

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

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 14-3-3?. Mechanistic studies revealed 14-3-3? dimerization as a key prerequisite, which could be dynamically induced via an allosteric effect. The selective inhibition of 14-3-3? 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 14-3-3?, and provide a distinctive PTM editing strategy which differs from current histone modification approaches.

SUBMITTER: Wan YJ

PROVIDER: S-EPMC6929985 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Publications

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

Wan Yan-Jun YJ Liao Li-Xi LX Liu Yang Y Yang Heng H Song Xiao-Min XM Wang Li-Chao LC Zhang Xiao-Wen XW Qian Yi Y Liu Dan D Shi Xiao-Meng XM Han Li-Wen LW Xia Qing Q Liu Ke-Chun KC Du Zhi-Yong ZY Jiang Yong Y Zhao Ming-Bo MB Zeng Ke-Wu KW Tu Peng-Fei PF

Theranostics 20200101 2

<b>Background:</b> 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. <b>Methods and Results:</b> In this study, we discovered a previously unexplored regulation mechanism for histone PTMs by targeting transcription regulation factor 14-3-3ζ. Mechanistic studies revealed ...[more]

PMID: 31903151

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Project description:Histones are abundant chromatin constituents carrying numerous post-translational modifications (PTMs). Such PTMs mediate a variety of biological functions, including recruitment of enzymatic readers, writers and erasers that modulate DNA replication, transcription and repair. Individual histone molecules contain multiple coexisting PTMs, some of which exhibit crosstalk, i.e. coordinated or mutually exclusive activities. Here, we present an integrated experimental and computational systems level molecular characterization of histone PTMs and PTM crosstalk. Using wild type and engineered mouse embryonic stem cells (mESCs) knocked out in components of the Polycomb Repressive Complex 2 (PRC2, Suz12(-/-)), PRC1 (Ring1A/B(-/-)) and (Dnmt1/3a/3b(-/-)) we performed comprehensive PTM analysis of histone H3 tails (50 aa) by utilizing quantitative middle-down proteome analysis by tandem mass spectrometry. We characterized combinatorial PTM features across the four mESC lines and then applied statistical data analysis to predict crosstalk between histone H3 PTMs. We detected an overrepresentation of positive crosstalk (codependent marks) between adjacent mono-methylated and acetylated marks, and negative crosstalk (mutually exclusive marks) among most of the seven characterized di- and tri-methylated lysine residues in the H3 tails. We report novel features of PTM interplay involving hitherto poorly characterized arginine methylation and lysine methylation sites, including H3R2me, H3R8me and H3K37me. Integration of the H3 data with RNAseq data by coabundance clustering analysis of histone PTMs and histone modifying enzymes revealed correlations between PTM and enzyme levels. We conclude that middle-down proteomics is a powerful tool to determine conserved or dynamic interdependencies between histone marks, which paves the way for detailed investigations of the histone code. Histone H3 PTM data is publicly available in the CrossTalkDB repository at http://crosstalkdb.bmb.sdu.dk.

Dataset Information

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

Publications

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

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