H3K14ac is linked to methylation of H3K9 by the triple Tudor domain of SETDB1

Renata Z. Jurkowska, Su Qin, Goran Kungulovski, Wolfram Tempel, Yanli Liu, Pavel Bashtrykov, Judith Stiefelmaier, Tomasz P. Jurkowski, Srikanth Kudithipudi, Sara Weirich, Raluca Tamas, Hong Wu, Ludmila Dombrovski, Peter Loppnau, Richard Reinhardt, Jinrong Min () and Albert Jeltsch ()
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Renata Z. Jurkowska: Stuttgart University
Su Qin: University of Toronto
Goran Kungulovski: Stuttgart University
Wolfram Tempel: University of Toronto
Yanli Liu: University of Toronto
Pavel Bashtrykov: Stuttgart University
Judith Stiefelmaier: Stuttgart University
Tomasz P. Jurkowski: Stuttgart University
Srikanth Kudithipudi: Stuttgart University
Sara Weirich: Stuttgart University
Raluca Tamas: Stuttgart University
Hong Wu: University of Toronto
Ludmila Dombrovski: University of Toronto
Peter Loppnau: University of Toronto
Richard Reinhardt: Max-Planck-Genomzentrum Köln
Jinrong Min: University of Toronto
Albert Jeltsch: Stuttgart University

Nature Communications, 2017, vol. 8, issue 1, 1-13

Abstract: Abstract SETDB1 is an essential H3K9 methyltransferase involved in silencing of retroviruses and gene regulation. We show here that its triple Tudor domain (3TD) specifically binds to doubly modified histone H3 containing K14 acetylation and K9 methylation. Crystal structures of 3TD in complex with H3K14ac/K9me peptides reveal that peptide binding and K14ac recognition occurs at the interface between Tudor domains (TD) TD2 and TD3. Structural and biochemical data demonstrate a pocket switch mechanism in histone code reading, because K9me1 or K9me2 is preferentially recognized by the aromatic cage of TD3, while K9me3 selectively binds to TD2. Mutations in the K14ac/K9me binding sites change the sub-nuclear localization of 3TD. ChIP-seq analyses show that SETDB1 is enriched at H3K9me3 regions and K9me3/K14ac is enriched at SETDB1 binding sites overlapping with LINE elements, suggesting that recruitment of the SETDB1 complex to K14ac/K9me regions has a role in silencing of active genomic regions.

Date: 2017
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DOI: 10.1038/s41467-017-02259-9

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