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Mechanism and regulation of acetylated histone binding by the tandem PHD finger of DPF3b

Nature volume 466, pages 258–262 (2010)Cite this article

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Abstract

Histone lysine acetylation and methylation have an important role during gene transcription in a chromatin context1,2. Knowledge concerning the types of protein modules that can interact with acetyl-lysine has so far been limited to bromodomains1. Recently, a tandem plant homeodomain (PHD) finger3 (PHD1–PHD2, or PHD12) of human DPF3b, which functions in association with the BAF chromatin remodelling complex to initiate gene transcription during heart and muscle development, was reported to bind histones H3 and H4 in an acetylation-sensitive manner4, making it the first alternative to bromodomains for acetyl-lysine binding5. Here we report the structural mechanism of acetylated histone binding by the double PHD fingers of DPF3b. Our three-dimensional solution structures and biochemical analysis of DPF3b highlight the molecular basis of the integrated tandem PHD finger, which acts as one functional unit in the sequence-specific recognition of lysine-14-acetylated histone H3 (H3K14ac). Whereas the interaction with H3 is promoted by acetylation at lysine 14, it is inhibited by methylation at lysine 4, and these opposing influences are important during transcriptional activation of the mouse DPF3b target genes Pitx2 and Jmjd1c. Binding of this tandem protein module to chromatin can thus be regulated by different histone modifications during the initiation of gene transcription.

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Figure 1: Three-dimensional structure of the tandem PHD finger of human DPF3b.
Figure 2: Structural mechanism of acetyl-lysine recognition by human DPF3b PHD12.
Figure 3: Distinct modes of acetyl-lysine and H3 recognition by DPF3b PHD12 and other protein modules.
Figure 4: Acetylation- and methylation-modulated histone H3 binding by DPF3b PHD12 is important for gene transcriptional activation.

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Accession codes

Primary accessions

Protein Data Bank

Data deposits

The structural coordinates of human DPF3b PHD12 in complex with H3K14ac, H3, H4-Nac, or H4K16ac peptides are deposited in the Protein Data Bank under accession codes 2kwj, 2kwk, 2kwn and 2kwo, respectively. Accession codes for the chemical shift assignments of the corresponding NMR structures deposited at the BioMagResBank are 16858, 16859, 16861 and 16865, respectively.

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Acknowledgements

We acknowledge the use of the NMR Facility at the New York Structural Biology Center. We thank S. Hearn of Cold Spring Harbor Laboratory microscopy facility for help with confocal microscopy study, and A. Buku and G. Gerona-Navarro for technical advice on peptide binding analysis. This work was supported by grants from the National Institutes of Health (M.-M.Z.).

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Author notes

  1. Lei Zeng and Qiang Zhang: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Structural and Chemical Biology, Mount Sinai School of Medicine, 1425 Madison Avenue, Box 1677, New York, New York 10029, USA,

    Lei Zeng, Qiang Zhang, Alexander N. Plotnikov, Martin J. Walsh & Ming-Ming Zhou

  2. Department of Paediatrics, Mount Sinai School of Medicine, 1425 Madison Avenue, New York, 10029, New York, USA

    SiDe Li & Martin J. Walsh

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  1. Lei Zeng
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Contributions

M.-M.Z. and M.J.W. designed the study; Q.Z. generated constructs and protein samples, and contributed to the immunofluorescence study; L.Z. determined the protein structures; A.N.P. contributed to the protein biochemistry study; L.Z. and Q.Z. performed protein and peptide binding study; S.L. and M.J.W. carried out the cell biology experiments; M.-M.Z. supervised the project; all authors contributed to manuscript preparation.

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Correspondence to Ming-Ming Zhou.

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The authors declare no competing financial interests.

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This file contains Supplementary Figures 1-12 with legends and Supplementary Tables 1-5. (PDF 8141 kb)

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Zeng, L., Zhang, Q., Li, S. et al. Mechanism and regulation of acetylated histone binding by the tandem PHD finger of DPF3b. Nature 466, 258–262 (2010). https://doi.org/10.1038/nature09139

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