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Insights into newly discovered marks and readers of epigenetic information

Nature Chemical Biology volume 12, pages 662–668 (2016)Cite this article

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Abstract

The field of chromatin biology has been advancing at an accelerated pace. Recent discoveries of previously uncharacterized sites and types of post-translational modifications (PTMs) and the identification of new sets of proteins responsible for the deposition, removal, and reading of these marks continue raising the complexity of an already exceedingly complicated biological phenomenon. In this Perspective article we examine the biological importance of new types and sites of histone PTMs and summarize the molecular mechanisms of chromatin engagement by newly discovered epigenetic readers. We also highlight the imperative role of structural insights in understanding PTM–reader interactions and discuss future directions to enhance the knowledge of PTM readout.

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Figure 1: Recognition of epigenetic marks by histone readers.
Figure 2: Modifications identified in histone proteins.
Figure 3: Novel acyllysine readers and their binding mechanisms.
Figure 4: New methyllysine readers.
Figure 5: Novel readers of unmodified histone H3.
Figure 6: Crosstalk of PTMs and paired readers.

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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. Jenuwein, T. & Allis, C.D. Translating the histone code. Science 293, 1074–1080 (2001).

    Article  CAS  PubMed  Google Scholar 

  3. Kouzarides, T. Chromatin modifications and their function. Cell 128, 693–705 (2007).

    Article  CAS  PubMed  Google Scholar 

  4. Chi, P., Allis, C.D. & Wang, G.G. Covalent histone modification—miswritten, misinterpreted and mis-erased in human cancers. Nat. Rev. Cancer 10, 457–469 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Polak, P. et al. Cell-of-origin chromatin organization shapes the mutational landscape of cancer. Nature 518, 360–364 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Shen, H. & Laird, P.W. Interplay between the cancer genome and epigenome. Cell 153, 38–55 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  8. Bannister, A.J. et al. Selective recognition of methylated lysine 9 on histone H3 by the HP1 chromo domain. Nature 410, 120–124 (2001).

    Article  CAS  PubMed  Google Scholar 

  9. Nielsen, P.R. et al. Structure of the HP1 chromodomain bound to histone H3 methylated at lysine 9. Nature 416, 103–107 (2002).

    Article  CAS  PubMed  Google Scholar 

  10. Jacobs, S.A. & Khorasanizadeh, S. Structure of HP1 chromodomain bound to a lysine 9-methylated histone H3 tail. Science 295, 2080–2083 (2002).

    Article  CAS  PubMed  Google Scholar 

  11. Li, H. et al. Molecular basis for site-specific read-out of histone H3K4me3 by the BPTF PHD finger of NURF. Nature 442, 91–95 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Peña, P.V. et al. Molecular mechanism of histone H3K4me3 recognition by plant homeodomain of ING2. Nature 442, 100–103 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Shi, X. et al. ING2 PHD domain links histone H3 lysine 4 methylation to active gene repression. Nature 442, 96–99 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Wysocka, J. et al. A PHD finger of NURF couples histone H3 lysine 4 trimethylation with chromatin remodelling. Nature 442, 86–90 (2006).

    Article  CAS  PubMed  Google Scholar 

  15. 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 

  16. 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 

  17. Yap, K.L. & Zhou, M.M. Keeping it in the family: diverse histone recognition by conserved structural folds. Crit. Rev. Biochem. Mol. Biol. 45, 488–505 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Rothbart, S.B. & Strahl, B.D. Interpreting the language of histone and DNA modifications. Biochim. Biophys. Acta 1839, 627–643 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Xie, Z. et al. Lysine succinylation and lysine malonylation in histones. Mol. Cell. Proteomics 11, 100–107 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. 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 

  21. Dai, L. et al. Lysine 2-hydroxyisobutyrylation is a widely distributed active histone mark. Nat. Chem. Biol. 10, 365–370 (2014).

    Article  CAS  PubMed  Google Scholar 

  22. Biterge, B., Richter, F., Mittler, G. & Schneider, R. Methylation of histone H4 at aspartate 24 by protein L-isoaspartate O-methyltransferase (PCMT1) links histone modifications with protein homeostasis. Sci. Rep. 4, 6674 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. 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 

  24. Guillemette, B. et al. H3 lysine 4 is acetylated at active gene promoters and is regulated by H3 lysine 4 methylation. PLoS Genet. 7, e1001354 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Zhang, X. et al. Peptidylarginine deiminase 2-catalyzed histone H3 arginine 26 citrullination facilitates estrogen receptor α target gene activation. Proc. Natl. Acad. Sci. USA 109, 13331–13336 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  26. Di Cerbo, V. et al. Acetylation of histone H3 at lysine 64 regulates nucleosome dynamics and facilitates transcription. eLife 3, e01632 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Lange, U.C. et al. Dissecting the role of H3K64me3 in mouse pericentromeric heterochromatin. Nat. Commun. 4, 2233 (2013).

    Article  CAS  PubMed  Google Scholar 

  28. Casadio, F. et al. H3R42me2a is a histone modification with positive transcriptional effects. Proc. Natl. Acad. Sci. USA 110, 14894–14899 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  29. Jang, S.M., Azebi, S., Soubigou, G. & Muchardt, C. DYRK1A phoshorylates histone H3 to differentially regulate the binding of HP1 isoforms and antagonize HP1-mediated transcriptional repression. EMBO Rep. 15, 686–694 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. 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 

  31. 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 

  32. 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 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. 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 

  35. Shanle, E.K. et al. Association of Taf14 with acetylated histone H3 directs gene transcription and the DNA damage response. Genes Dev. 29, 1795–1800 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Andrews, F.H., Shanle, E.K., Strahl, B.D. & Kutateladze, T.G. The essential role of acetyllysine binding by the YEATS domain in transcriptional regulation. Transcription 7, 14–20 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. 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 

  38. Vollmuth, F. & Geyer, M. Interaction of propionylated and butyrylated histone H3 lysine marks with Brd4 bromodomains. Angew. Chem. Int. Edn. Engl. 49, 6768–6772 (2010).

    Article  CAS  Google Scholar 

  39. Su, X. et al. Molecular basis underlying histone H3 lysine-arginine methylation pattern readout by Spin/Ssty repeats of Spindlin1. Genes Dev. 28, 622–636 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Yang, N. et al. Distinct mode of methylated lysine-4 of histone H3 recognition by tandem tudor-like domains of Spindlin1. Proc. Natl. Acad. Sci. USA 109, 17954–17959 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  41. Wang, W. et al. Nucleolar protein Spindlin1 recognizes H3K4 methylation and stimulates the expression of rRNA genes. EMBO Rep. 12, 1160–1166 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Law, J.A. et al. Polymerase IV occupancy at RNA-directed DNA methylation sites requires SHH1. Nature 498, 385–389 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Chen, S. et al. The PZP domain of AF10 senses unmodified H3K27 to regulate DOT1L-mediated methylation of H3K79. Mol. Cell 60, 319–327 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Klein, B.J. et al. Bivalent interaction of the PZP domain of BRPF1 with the nucleosome impacts chromatin dynamics and acetylation. Nucleic Acids Res. 44, 472–484 (2016).

    Article  CAS  PubMed  Google Scholar 

  45. Qin, S. et al. Recognition of unmodified histone H3 by the first PHD finger of bromodomain-PHD finger protein 2 provides insights into the regulation of histone acetyltransferases monocytic leukemic zinc-finger protein (MOZ) and MOZ-related factor (MORF). J. Biol. Chem. 286, 36944–36955 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Wen, H. et al. ZMYND11 links histone H3.3K36me3 to transcription elongation and tumour suppression. Nature 508, 263–268 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Li, S. et al. Structural basis for the unique multivalent readout of unmodified H3 Tail by Arabidopsis ORC1b BAH-PHD cassette. Structure 24, 486–494 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Du, J. et al. Dual binding of chromomethylase domains to H3K9me2-containing nucleosomes directs DNA methylation in plants. Cell 151, 167–180 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Helin, K. & Dhanak, D. Chromatin proteins and modifications as drug targets. Nature 502, 480–488 (2013).

    Article  CAS  PubMed  Google Scholar 

  50. Arrowsmith, C.H., Bountra, C., Fish, P.V., Lee, K. & Schapira, M. Epigenetic protein families: a new frontier for drug discovery. Nat. Rev. Drug Discov. 11, 384–400 (2012).

    Article  CAS  PubMed  Google Scholar 

  51. Fischle, W., Wang, Y. & Allis, C.D. Binary switches and modification cassettes in histone biology and beyond. Nature 425, 475–479 (2003).

    Article  CAS  PubMed  Google Scholar 

  52. Andrews, F.H., Gatchalian, J., Krajewski, K., Strahl, B.D. & Kutateladze, T.G. Regulation of methyllysine readers through phosphorylation. ACS Chem. Biol. 11, 547–553 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Gatchalian, J. et al. Chromatin condensation and recruitment of PHD finger proteins to histone H3K4me3 are mutually exclusive. Nucleic Acids Res. http://dx.doi.org/10.1093/nar/gkw193 (2016).

  54. Zaidi, S.K. et al. Mitotic bookmarking of genes: a novel dimension to epigenetic control. Nat. Rev. Genet. 11, 583–589 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Zhao, R., Nakamura, T., Fu, Y., Lazar, Z. & Spector, D.L. Gene bookmarking accelerates the kinetics of post-mitotic transcriptional re-activation. Nat. Cell Biol. 13, 1295–1304 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

Research in T.G.K.'s laboratory is supported by US National Institutes of Health (NIH) grants GM101664, GM106416, and GM100907. B.D.S. is supported by grants from the NIH and the US National Science Foundation (GM110058 and MCB1330320). F.H.A. was supported by NIH grant T32AA007464 and an AHA postdoctoral fellowship.

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Authors and Affiliations

  1. Department of Pharmacology, University of Colorado School of Medicine, Aurora, Colorado, USA

    Forest H Andrews & Tatiana G Kutateladze

  2. Department of Biochemistry and Biophysics, the University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA

    Brian D Strahl

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Correspondence to Tatiana G Kutateladze.

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Andrews, F., Strahl, B. & Kutateladze, T. Insights into newly discovered marks and readers of epigenetic information. Nat Chem Biol 12, 662–668 (2016). https://doi.org/10.1038/nchembio.2149

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