The tandem PHD (plant homeodomain) fingers of the CHD4 (chromodomain helicase DNA-binding protein 4) ATPase are epigenetic readers that bind either unmodified histone H3 tails or H3K9me3 (histone H3 trimethylated at Lys9). This dual function is necessary for the transcriptional and chromatin remodelling activities of the NuRD (nucleosome remodelling and deacetylase) complex. In the present paper, we show that calixarene-based supramolecular hosts disrupt binding of the CHD4 PHD2 finger to H3K9me3, but do not affect the interaction of this protein with the H3K9me0 (unmodified histone H3) tail. A similar inhibitory effect, observed for the association of chromodomain of HP1γ (heterochromatin protein 1γ) with H3K9me3, points to a general mechanism of methyl-lysine caging by calixarenes and suggests a high potential for these compounds in biochemical applications. Immunofluorescence analysis reveals that the supramolecular agents induce changes in chromatin organization that are consistent with their binding to and disruption of H3K9me3 sites in living cells. The results of the present study suggest that the aromatic macrocyclic hosts can be used as a powerful new tool for characterizing methylation-driven epigenetic mechanisms.
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Research Article|
April 11 2014
Inhibition of histone binding by supramolecular hosts
Hillary F. Allen;
Hillary F. Allen
1
*Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO 80045, U.S.A.
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Kevin D. Daze;
Kevin D. Daze
1
†Department of Chemistry, University of Victoria, Victoria, BC, Canada, V8W 3V6
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Takashi Shimbo;
Takashi Shimbo
‡Laboratory of Molecular Carcinogenesis, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, U.S.A.
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Anne Lai;
Anne Lai
‡Laboratory of Molecular Carcinogenesis, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, U.S.A.
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Catherine A. Musselman;
Catherine A. Musselman
*Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO 80045, U.S.A.
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Jennifer K. Sims;
Jennifer K. Sims
‡Laboratory of Molecular Carcinogenesis, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, U.S.A.
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Paul A. Wade;
Paul A. Wade
‡Laboratory of Molecular Carcinogenesis, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, U.S.A.
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Fraser Hof;
Fraser Hof
2
†Department of Chemistry, University of Victoria, Victoria, BC, Canada, V8W 3V6
2Correspondence may be addressed to either of these authors (email fhof@uvic.ca or tatiana.kutateladze@ucdenver.edu).
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Tatiana G. Kutateladze
Tatiana G. Kutateladze
2
*Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO 80045, U.S.A.
2Correspondence may be addressed to either of these authors (email fhof@uvic.ca or tatiana.kutateladze@ucdenver.edu).
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Publisher: Portland Press Ltd
Received:
January 29 2014
Revision Received:
February 27 2014
Accepted:
February 28 2014
Accepted Manuscript online:
February 28 2014
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2014 Biochemical Society
2014
Biochem J (2014) 459 (3): 505–512.
Article history
Received:
January 29 2014
Revision Received:
February 27 2014
Accepted:
February 28 2014
Accepted Manuscript online:
February 28 2014
Citation
Hillary F. Allen, Kevin D. Daze, Takashi Shimbo, Anne Lai, Catherine A. Musselman, Jennifer K. Sims, Paul A. Wade, Fraser Hof, Tatiana G. Kutateladze; Inhibition of histone binding by supramolecular hosts. Biochem J 1 May 2014; 459 (3): 505–512. doi: https://doi.org/10.1042/BJ20140145
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