Title

Citrullination/Methylation Crosstalk on Histone H3 Regulates ER-Target Gene Transcription.

UMMS Affiliation

Thompson Lab; Department of Biochemistry and Molecular Pharmacology; Program in Chemical Biology

Publication Date

2017-06-16

Document Type

Article

Disciplines

Biochemistry | Enzymes and Coenzymes | Medicinal-Pharmaceutical Chemistry

Abstract

Posttranslational modifications of histone tails are a key contributor to epigenetic regulation. Histone H3 Arg26 and Lys27 are both modified by multiple enzymes, and their modifications have profound effects on gene expression. Citrullination of H3R26 by PAD2 and methylation of H3K27 by PRC2 have opposing downstream impacts on gene regulation; H3R26 citrullination activates gene expression, and H3K27 methylation represses gene expression. Both of these modifications are drivers of a variety of cancers, and their writer enzymes, PAD2 and EZH2, are the targets of drug therapies. After biochemical and cell-based analysis of these modifications, a negative crosstalk interaction is observed. Methylation of H3K27 slows citrullination of H3R26 30-fold, whereas citrullination of H3R26 slows methylation 30,000-fold. Examination of the mechanism of this crosstalk interaction uncovered a change in structure of the histone tail upon citrullination which prevents methylation by the PRC2 complex. This mechanism of crosstalk is reiterated in cell lines using knockdowns and inhibitors of both enzymes. Based our data, we propose a model in which, after H3 Cit26 formation, H3K27 demethylases are recruited to the chromatin to activate transcription. In total, our studies support the existence of crosstalk between citrullination of H3R26 and methylation of H3K27.

Keywords

Citrulline, Gene Expression Regulation, Neoplastic, Histones, Humans, Hydrolases, Methylation, Models, Theoretical, Polycomb Repressive Complex 2, Protein-Arginine Deiminases, Receptor Cross-Talk, Transcription, Genetic, Transcriptional Activation

DOI of Published Version

10.1021/acschembio.7b00241

Source

ACS Chem Biol. 2017 Jun 16;12(6):1691-1702. doi: 10.1021/acschembio.7b00241. Epub 2017 May 9. Link to article on publisher's site

Journal/Book/Conference Title

ACS Chemical Biology

Related Resources

Link to article in PubMed

PubMed ID

28485572

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