Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Selective recognition of histone crotonylation by double PHD fingers of MOZ and DPF2

Nature Chemical Biology volume 12, pages 1111–1118 (2016)Cite this article

Subjects

Abstract

Recognition of histone covalent modifications by 'reader' modules constitutes a major mechanism for epigenetic regulation. A recent upsurge of newly discovered histone lysine acylations, such as crotonylation (Kcr), butyrylation (Kbu), and propionylation (Kpr), greatly expands the coding potential of histone lysine modifications. Here we demonstrate that the histone acetylation-binding double PHD finger (DPF) domains of human MOZ (also known as KAT6A) and DPF2 (also known as BAF45d) accommodate a wide range of histone lysine acylations with the strongest preference for Kcr. Crystal structures of the DPF domain of MOZ in complex with H3K14cr, H3K14bu, and H3K14pr peptides reveal that these non-acetyl acylations are anchored in a hydrophobic 'dead-end' pocket with selectivity for crotonylation arising from intimate encapsulation and an amide-sensing hydrogen bonding network. Immunofluorescence and chromatin immunoprecipitation (ChIP)–quantitative PCR (qPCR) showed that MOZ and H3K14cr colocalize in a DPF-dependent manner. Our studies call attention to a new regulatory mechanism centered on histone crotonylation readout by DPF family members.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Identification of MOZDPF and DPF2DPF as favorable readers of Kcr.
Figure 2: Molecular details for H3K14cr readout by MOZDPF.
Figure 3: Recognition of different histone H3K14 acylations by MOZDPF.
Figure 4: Size-selective recognition of H3K14cr by MOZDPF.
Figure 5: Recognition of H3K14cr by DPF2-mimicking MOZDPF.
Figure 6: Mutagenesis and colocalization studies.

Similar content being viewed by others

Accession codes

Primary accessions

Protein Data Bank

Referenced accessions

Protein Data Bank

References

  1. Strahl, B.D. & Allis, C.D. The language of covalent histone modifications. Nature 403, 41–45 (2000).

    Article  CAS  PubMed  Google Scholar 

  2. Taverna, S.D., Li, H., Ruthenburg, A.J., Allis, C.D. & Patel, D.J. How chromatin-binding modules interpret histone modifications: lessons from professional pocket pickers. Nat. Struct. Mol. Biol. 14, 1025–1040 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Musselman, C.A., Lalonde, M.E., Côté, J. & Kutateladze, T.G. Perceiving the epigenetic landscape through histone readers. Nat. Struct. Mol. Biol. 19, 1218–1227 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Patel, D.J. & Wang, Z. Readout of epigenetic modifications. Annu. Rev. Biochem. 82, 81–118 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Verdin, E. & Ott, M. 50 years of protein acetylation: from gene regulation to epigenetics, metabolism and beyond. Nat. Rev. Mol. Cell Biol. 16, 258–264 (2015).

    Article  CAS  PubMed  Google Scholar 

  6. Huang, H., Sabari, B.R., Garcia, B.A., Allis, C.D. & Zhao, Y. SnapShot: histone modifications. Cell 159, 458–458.e1 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Huang, H., Lin, S., Garcia, B.A. & Zhao, Y. Quantitative proteomic analysis of histone modifications. Chem. Rev. 115, 2376–2418 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Tan, M. et al. Identification of 67 histone marks and histone lysine crotonylation as a new type of histone modification. Cell 146, 1016–1028 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Montellier, E., Rousseaux, S., Zhao, Y. & Khochbin, S. Histone crotonylation specifically marks the haploid male germ cell gene expression program: post-meiotic male-specific gene expression. BioEssays 34, 187–193 (2012).

    Article  CAS  PubMed  Google Scholar 

  10. Sabari, B.R. et al. Intracellular crotonyl-CoA stimulates transcription through p300-catalyzed histone crotonylation. Mol. Cell 58, 203–215 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Dhalluin, C. et al. Structure and ligand of a histone acetyltransferase bromodomain. Nature 399, 491–496 (1999).

    Article  CAS  PubMed  Google Scholar 

  12. Lange, M. et al. Regulation of muscle development by DPF3, a novel histone acetylation and methylation reader of the BAF chromatin remodeling complex. Genes Dev. 22, 2370–2384 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Zeng, L. et al. Mechanism and regulation of acetylated histone binding by the tandem PHD finger of DPF3b. Nature 466, 258–262 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Li, Y. et al. AF9 YEATS domain links histone acetylation to DOT1L-mediated H3K79 methylation. Cell 159, 558–571 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Li, Y. et al. Molecular Coupling of Histone Crotonylation and Active Transcription by AF9 YEATS Domain. Mol. Cell 62, 181–193 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Zhao, D. et al. YEATS2 is a selective histone crotonylation reader. Cell Res. 26, 629–632 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Andrews, F.H. et al. The Taf14 YEATS domain is a reader of histone crotonylation. Nat. Chem. Biol. 12, 396–398 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Qiu, Y. et al. Combinatorial readout of unmodified H3R2 and acetylated H3K14 by the tandem PHD finger of MOZ reveals a regulatory mechanism for HOXA9 transcription. Genes Dev. 26, 1376–1391 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Ali, M. et al. Tandem PHD fingers of MORF/MOZ acetyltransferases display selectivity for acetylated histone H3 and are required for the association with chromatin. J. Mol. Biol. 424, 328–338 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Dreveny, I. et al. The double PHD finger domain of MOZ/MYST3 induces α-helical structure of the histone H3 tail to facilitate acetylation and methylation sampling and modification. Nucleic Acids Res. 42, 822–835 (2014).

    Article  CAS  PubMed  Google Scholar 

  21. Borrow, J. et al. The translocation t(8;16) (p11;p13) of acute myeloid leukaemia fuses a putative acetyltransferase to the CREB-binding protein. Nat. Genet. 14, 33–41 (1996).

    Article  CAS  PubMed  Google Scholar 

  22. Champagne, N. et al. Identification of a human histone acetyltransferase related to monocytic leukemia zinc finger protein. J. Biol. Chem. 274, 28528–28536 (1999).

    Article  CAS  PubMed  Google Scholar 

  23. Perez-Campo, F.M., Costa, G., Lie-a-Ling, M., Kouskoff, V. & Lacaud, G. The MYSTerious MOZ, a histone acetyltransferase with a key role in haematopoiesis. Immunology 139, 161–165 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Yang, X.J. MOZ and MORF acetyltransferases: Molecular interaction, animal development and human disease. Biochim. Biophys. Acta 1853, 1818–1826 (2015).

    Article  CAS  PubMed  Google Scholar 

  25. Wu, J.I. Diverse functions of ATP-dependent chromatin remodeling complexes in development and cancer. Acta Biochim. Biophys. Sin. (Shanghai) 44, 54–69 (2012).

    Article  CAS  Google Scholar 

  26. Xie, Z. et al. Metabolic Regulation of Gene Expression by Histone Lysine β-Hydroxybutyrylation. Mol. Cell 62, 194–206 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Arib, G. & Akhtar, A. Multiple facets of nuclear periphery in gene expression control. Curr. Opin. Cell Biol. 23, 346–353 (2011).

    Article  CAS  PubMed  Google Scholar 

  28. Feldman, J.L., Baeza, J. & Denu, J.M. Activation of the protein deacetylase SIRT6 by long-chain fatty acids and widespread deacylation by mammalian sirtuins. J. Biol. Chem. 288, 31350–31356 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Bao, X. et al. Identification of 'erasers' for lysine crotonylated histone marks using a chemical proteomics approach. eLife 3, 2999 (2014).

    Article  Google Scholar 

  30. Ruthenburg, A.J., Li, H., Patel, D.J. & Allis, C.D. Multivalent engagement of chromatin modifications by linked binding modules. Nat. Rev. Mol. Cell Biol. 8, 983–994 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Li, Y. & Li, H. Many keys to push: diversifying the 'readership' of plant homeodomain fingers. Acta Biochim. Biophys. Sin. (Shanghai) 44, 28–39 (2012).

    Article  CAS  Google Scholar 

  32. Li, H. et al. Structural basis for lower lysine methylation state-specific readout by MBT repeats of L3MBTL1 and an engineered PHD finger. Mol. Cell 28, 677–691 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Flynn, E.M. et al. A Subset of Human Bromodomains Recognizes Butyryllysine and Crotonyllysine Histone Peptide Modifications. Structure 23, 1801–1814 (2015).

    Article  CAS  PubMed  Google Scholar 

  34. Carlson, S. & Glass, K.C. The MOZ histone acetyltransferase in epigenetic signaling and disease. J. Cell. Physiol. 229, 1571–1574 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Vu, L.P. et al. PRMT4 blocks myeloid differentiation by assembling a methyl-RUNX1-dependent repressor complex. Cell Rep. 5, 1625–1638 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Cruickshank, V.A. et al. SWI/SNF Subunits SMARCA4, SMARCD2 and DPF2 Collaborate in MLL-Rearranged Leukaemia Maintenance. PLoS One 10, e0142806 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  37. Otwinowski, Z. & Minor, W. Processing of X-ray diffraction data collected in oscillation mode. Methods Enzymol. 276, 307–326 (1997).

    Article  CAS  PubMed  Google Scholar 

  38. Vagin, A. & Teplyakov, A. Molecular replacement with MOLREP. Acta Crystallogr. D Biol. Crystallogr. 66, 22–25 (2010).

    Article  CAS  PubMed  Google Scholar 

  39. Adams, P.D. et al. PHENIX: a comprehensive Python-based system for macromolecular structure solution. Acta Crystallogr. D Biol. Crystallogr. 66, 213–221 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Emsley, P. & Cowtan, K. Coot: model-building tools for molecular graphics. Acta Crystallogr. D Biol. Crystallogr. 60, 2126–2132 (2004).

    Article  PubMed  CAS  Google Scholar 

  41. Ruthenburg, A.J. et al. Recognition of a mononucleosomal histone modification pattern by BPTF via multivalent interactions. Cell 145, 692–706 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Kim, C.H., Kang, M., Kim, H.J., Chatterjee, A. & Schultz, P.G. Site-specific incorporation of ɛ-N-crotonyllysine into histones. Angew. Chem. Int. Edn Engl. 51, 7246–7249 (2012).

    Article  CAS  Google Scholar 

  43. Gattner, M.J., Vrabel, M. & Carell, T. Synthesis of ɛ-N-propionyl-, ɛ-N-butyryl-, and ɛ-N-crotonyl-lysine containing histone H3 using the pyrrolysine system. Chem. Commun. (Camb.) 49, 379–381 (2013).

    Article  CAS  Google Scholar 

  44. Neumann, H. et al. A method for genetically installing site-specific acetylation in recombinant histones defines the effects of H3 K56 acetylation. Mol. Cell 36, 153–163 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Dyer, P.N. et al. Reconstitution of nucleosome core particles from recombinant histones and DNA. Methods Enzymol. 375, 23–44 (2004).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank Z. Chen for critical comments. We thank the staff members at beamline BL17U of the Shanghai Synchrotron Radiation Facility and S. Fan at Tsinghua Center for Structural Biology for their assistance in data collection, and the China National Center for Protein Sciences Beijing for providing facility support. This work was supported by grants from the Ministry of Science and Technology of China (2016YFA0500700 and 2015CB910503), the National Natural Science Foundation of China (91519304), and the Tsinghua University Initiative Scientific Research Program to H.L. We acknowledge support from The Rockefeller University to C.D.A., and the US National Institute of General Medicine to C.D.A. (GM040922), to Y.Z. (GM105933, DK107868, and GM115961), and to T.P. (GM112365).

Author information

Author notes

  1. Tatyana Panchenko

    Present address: Present address: Perlmutter Cancer Center, New York University, New York, New York, USA.,

Authors and Affiliations

  1. Department of Basic Medical Sciences, MOE Key Laboratory of Protein Sciences, Beijing Advanced Innovation Center for Structural Biology, School of Medicine, Tsinghua University, Beijing, China

    Xiaozhe Xiong, Shuang Yang, Shuai Zhao, Peiqiang Yan, Yuanyuan Li & Haitao Li

  2. Laboratory of Chromatin Biology and Epigenetics, The Rockefeller University, New York, New York, USA

    Tatyana Panchenko & C David Allis

  3. School of Life Sciences, Tsinghua University, Beijing, China

    Peiqiang Yan, Wenhao Zhang & Wei Xie

  4. Tsinghua-Peking Joint Center for Life Sciences, Tsinghua University, Beijing, China

    Wenhao Zhang, Wei Xie, Yuanyuan Li & Haitao Li

  5. Ben May Department of Cancer Research, The University of Chicago, Chicago, Illinois, USA

    Yingming Zhao

  6. Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, China

    Haitao Li

Authors
  1. Xiaozhe Xiong
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Tatyana Panchenko
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Shuang Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Shuai Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Peiqiang Yan
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Wenhao Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Wei Xie
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Yuanyuan Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Yingming Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. C David Allis
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Haitao Li
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

H.L. conceived and designed the study; X.X. designed and performed most of the experiments under the guidance of H.L. Y.L. discovered the crotonyllysine reader activity of DPF domain. T.P. performed the designer nucleosome pulldown assay under the guidance of C.D.A. S.Y., P.Y., S.Z. and Y.L. helped with binding and crystallographic experiments. W.Z., W.X., Y.Z. and C.D.A. provided expertise and critical feedback; H.L. and X.X. wrote the manuscript with input from other authors.

Corresponding author

Correspondence to Haitao Li.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Results, Supplementary Tables 1–3 and Supplementary Figures 1–6. (PDF 1783 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Xiong, X., Panchenko, T., Yang, S. et al. Selective recognition of histone crotonylation by double PHD fingers of MOZ and DPF2. Nat Chem Biol 12, 1111–1118 (2016). https://doi.org/10.1038/nchembio.2218

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nchembio.2218

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing