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  • Review Article
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Metabolic regulation of gene expression through histone acylations

Nature Reviews Molecular Cell Biology volume 18, pages 90–101 (2017)Cite this article

Subjects

Key Points

  • Eight new types of histone short-chain Lys acylations have been discovered in the past few years, which include Lys propionylation (Kpr), Lys butyrylation (Kbu), Lys 2-hydroxyisobutyrylation (Khib), Lys succinylation (Ksucc), Lys malonylation (Kma), Lys glutarylation (Kglu), Lys crotonylation (Kcr) and Lys β-hydroxybutyrylation (Kbhb).

  • Histone Lys acylations are regulated by acyltransferases and deacylases.

  • Histone Lys acylations are modulated by the cellular metabolism of cognate short-chain acyl-CoA species.

  • The novel histone Lys acylations are recognized by specific protein domains and can be differentiated from Lys acetylation.

  • Histone Lys acylations mark transcriptionally active genes and function in different physiological processes, such as signal-dependent gene activation, spermatogenesis, tissue injury and metabolic stress.

Abstract

Eight types of short-chain Lys acylations have recently been identified on histones: propionylation, butyrylation, 2-hydroxyisobutyrylation, succinylation, malonylation, glutarylation, crotonylation and β-hydroxybutyrylation. Emerging evidence suggests that these histone modifications affect gene expression and are structurally and functionally different from the widely studied histone Lys acetylation. In this Review, we discuss the regulation of non-acetyl histone acylation by enzymatic and metabolic mechanisms, the acylation 'reader' proteins that mediate the effects of different acylations and their physiological functions, which include signal-dependent gene activation, spermatogenesis, tissue injury and metabolic stress. We propose a model to explain our present understanding of how differential histone acylation is regulated by the metabolism of the different acyl-CoA forms, which in turn modulates the regulation of gene expression.

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Figure 1: Identifying Lys acylations.
Figure 2: Structure of Lys acylations and their distribution on histones.
Figure 3: Writers and erasers of Lys acylations.
Figure 4: The YEATS domain proteins share a common mechanism for crotonyl-Lys preference.
Figure 5: Metabolic regulation of histone acylation.
Figure 6: The functions of differential histone acylation.

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References

  1. Dawson, M. A. & Kouzarides, T. Cancer epigenetics: from mechanism to therapy. Cell 150, 12–27 (2012).

    Article  CAS  PubMed  Google Scholar 

  2. Pavlova, N. N. & Thompson, C. B. The emerging hallmarks of cancer metabolism. Cell Metab. 23, 27–47 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Ronan, J. L., Wu, W. & Crabtree, G. R. From neural development to cognition: unexpected roles for chromatin. Nat. Rev. Genet. 14, 347–359 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Lewis, P. W. et al. Inhibition of PRC2 activity by a gain-of-function H3 mutation found in pediatric glioblastoma. Science 340, 857–861 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Lu, C. et al. Histone H3K36 mutations promote sarcomagenesis through altered histone methylation landscape. Science 352, 844–849 (2016).

    Article  CAS  PubMed  PubMed Central  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. Chen, Y. et al. Lysine propionylation and butyrylation are novel post-translational modifications in histones. Mol. Cell. Proteomics 6, 812–819 (2007). This study describes the first identification and validation of histone Kpr and Kbu.

    Article  CAS  PubMed  Google Scholar 

  8. Dai, L. Z. et al. Lysine 2-hydroxyisobutyrylation is a widely distributed active histone mark. Nat. Chem. Biol. 10, 365–370 (2014). The first study to identify and characterize the epigenetic function of histone Khib.

    Article  CAS  PubMed  Google Scholar 

  9. 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 

  10. Tan, M. J. et al. Lysine glutarylation is a protein posttranslational modification regulated by SIRT5. Cell Metab. 19, 605–617 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Tan, M. J. et al. Identification of 67 histone marks and histone lysine crotonylation as a new type of histone modification. Cell 146, 1015–1027 (2011). The authors identify and characterize the epigenetic function of histone Kcr.

    Article  CAS  Google Scholar 

  12. Xie, Z. et al. Metabolic regulation of gene expression by histone lysine β-hydroxybutyrylation. Mol. Cell 62, 194–206 (2016). A study that reports Kbhb as a new type of histone modification that is closely associated with ketone body metabolism.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Choudhary, C., Weinert, B. T., Nishida, Y., Verdin, E. & Mann, M. The growing landscape of lysine acetylation links metabolism and cell signalling. Nat. Rev. Mol. Cell Biol. 15, 536–550 (2014).

    Article  CAS  PubMed  Google Scholar 

  14. Phillips, D. M. The presence of acetyl groups of histones. Biochem. J. 87, 258–263 (1963).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Allfrey, V. G., Faulkner, R. & Mirsky, A. E. Acetylation and methylation of histones and their possible role in regulation of RNA synthesis. Proc. Natl Acad. Sci. USA 51, 786–794 (1964).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Fan, J., Krautkramer, K. A., Feldman, J. L. & Denu, J. M. Metabolic regulation of histone post-translational modifications. ACS Chem. Biol. 10, 95–108 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Etchegaray, J. P. & Mostoslavsky, R. Interplay between metabolism and epigenetics: a nuclear adaptation to environmental changes. Mol. Cell 62, 695–711 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Su, X., Wellen, K. E. & Rabinowitz, J. D. Metabolic control of methylation and acetylation. Curr. Opin. Chem. Biol. 30, 52–60 (2016).

    Article  CAS  PubMed  Google Scholar 

  19. Zhang, Y., Fonslow, B. R., Shan, B., Baek, M. C. & Yates, J. R. III. Protein analysis by shotgun/bottom-up proteomics. Chem. Rev. 113, 2343–2394 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Olsen, J. V. & Mann, M. Status of large-scale analysis of post-translational modifications by mass spectrometry. Mol. Cell. Proteomics 12, 3444–3452 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Kim, S. C. et al. Substrate and functional diversity of lysine acetylation revealed by a proteomics survey. Mol. Cell 23, 607–618 (2006).

    Article  CAS  PubMed  Google Scholar 

  22. Peng, C. et al. The first identification of lysine malonylation substrates and its regulatory enzyme. Mol. Cell. Proteomics 10, M111.012658 (2011). The first study to establish Kma as a new type of protein modification.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  23. Tsur, D., Tanner, S., Zandi, E., Bafna, V. & Pevzner, P. A. Identification of post-translational modifications by blind search of mass spectra. Nat. Biotechnol. 23, 1562–1567 (2005).

    Article  CAS  PubMed  Google Scholar 

  24. Hansen, B. T., Davey, S. W., Ham, A. J. & Liebler, D. C. P-Mod: an algorithm and software to map modifications to peptide sequences using tandem MS data. J. Proteome Res. 4, 358–368 (2005).

    Article  CAS  PubMed  Google Scholar 

  25. Chen, Y., Chen, W., Cobb, M. H. & Zhao, Y. PTMap — a sequence alignment software for unrestricted, accurate, and full-spectrum identification of post-translational modification sites. Proc. Natl Acad. Sci. USA 106, 761–766 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Chick, J. M. et al. A mass-tolerant database search identifies a large proportion of unassigned spectra in shotgun proteomics as modified peptides. Nat. Biotechnol. 33, 743–749 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Moellering, R. E. & Cravatt, B. F. Functional lysine modification by an intrinsically reactive primary glycolytic metabolite. Science 341, 549–553 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Wagner, G. R. & Payne, R. M. Widespread and enzyme-independent Nε-acetylation and Nε-succinylation of proteins in the chemical conditions of the mitochondrial matrix. J. Biol. Chem. 288, 29036–29045 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Weinert, B. T., Moustafa, T., Iesmantavicius, V., Zechner, R. & Choudhary, C. Analysis of acetylation stoichiometry suggests that SIRT3 repairs nonenzymatic acetylation lesions. EMBO J. 34, 2620–2632 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Weinert, B. T. et al. Acetylation dynamics and stoichiometry in Saccharomyces cerevisiae. Mol. Syst. Biol. 10, 716 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. Lee, K. K. & Workman, J. L. Histone acetyltransferase complexes: one size doesn't fit all. Nat. Rev. Mol. Cell Biol. 8, 284–295 (2007).

    Article  CAS  PubMed  Google Scholar 

  32. Roth, S. Y., Denu, J. M. & Allis, C. D. Histone acetyltransferases. Annu. Rev. Biochem. 70, 81–120 (2001).

    Article  CAS  PubMed  Google Scholar 

  33. Bannister, A. J. & Kouzarides, T. The CBP co-activator is a histone acetyltransferase. Nature 384, 641–643 (1996).

    Article  CAS  PubMed  Google Scholar 

  34. Ogryzko, V. V., Schiltz, R. L., Russanova, V., Howard, B. H. & Nakatani, Y. The transcriptional coactivators p300 and CBP are histone acetyltransferases. Cell 87, 953–959 (1996).

    Article  CAS  PubMed  Google Scholar 

  35. Cheng, Z. et al. Molecular characterization of propionyllysines in non-histone proteins. Mol. Cell. Proteomics 8, 45–52 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Sabari, B. R. et al. Intracellular crotonyl-CoA stimulates transcription through p300-catalyzed histone crotonylation. Mol. Cell 58, 203–215 (2015). This study demonstrates that p300-mediated histone Kcr activates gene transcription, which is regulated by the cellular concentration of crotonyl-CoA.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Kaczmarska, Z. et al. Structure of p300 in complex with acyl-CoA variants. Nat. Chem. Biol. http://dx.doi.org/10.1038/nchembio.2217 (2016).

  38. Hu, A., Britton, L. M. & Garcia, B. A. Investigating the specificity of histone acetyltransferase activity for producing rare modifications on histones using mass spectrometry. The 62nd Annu. Am. Soc. Mass Spectrom. Conference Mass Spectrom. Allied Top., Baltimore, MD. https://www.abstracts.asms.org/pages/dashboard.html#/conference/252/toc/252/details (2014).

    Google Scholar 

  39. Yu-Ying, Y., Markus, G. & Howard, H. C. Identification of lysine acetyltransferase p300 substrates using 4-pentynoyl-coenzyme A and bioorthogonal proteomics. Bioorg. Med. Chem. Lett. 21, 4976–4979 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  40. Berndsen, C. E., Albaugh, B. N., Tan, S. & Denu, J. M. Catalytic mechanism of a MYST family histone acetyltransferase. Biochemistry 46, 623–629 (2007).

    Article  CAS  PubMed  Google Scholar 

  41. Leemhuis, H., Packman, L. C., Nightingale, K. P. & Hollfelder, F. The human histone acetyltransferase P/CAF is a promiscuous histone propionyltransferase. Chembiochem 9, 499–503 (2008).

    Article  CAS  PubMed  Google Scholar 

  42. Ringel, A. E. & Wolberger, C. Structural basis for acyl group discrimination by human Gcn5L2. Acta Crystallogr. D Struct. Biol. 72, 841–848 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. de Ruijter, A. J., van Gennip, A. H., Caron, H. N., Kemp, S. & van Kuilenburg, A. B. Histone deacetylases (HDACs): characterization of the classical HDAC family. Biochem. J. 370, 737–749 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Jing, H. & Lin, H. Sirtuins in epigenetic regulation. Chem. Rev. 115, 2350–2375 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Smith, B. C. & Denu, J. M. Acetyl-lysine analog peptides as mechanistic probes of protein deacetylases. J. Biol. Chem. 282, 37256–37265 (2007).

    Article  CAS  PubMed  Google Scholar 

  46. Imai, S., Armstrong, C. M., Kaeberlein, M. & Guarente, L. Transcriptional silencing and longevity protein Sir2 is an NAD-dependent histone deacetylase. Nature 403, 795–800 (2000).

    Article  CAS  PubMed  Google Scholar 

  47. Du, J. T. et al. Sirt5 Is a NAD-dependent protein lysine demalonylase and desuccinylase. Science 334, 806–809 (2011). Together with reference 22, these studies show that SIRT5 has robust desuccinylase and demalonylase activities.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Park, J. et al. SIRT5-mediated lysine desuccinylation impacts diverse metabolic pathways. Mol. Cell 50, 919–930 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. 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). A systematic study of the enzymatic activities of mammalian sirtuins against different histone Lys acylations.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Barber, M. F. et al. SIRT7 links H3K18 deacetylation to maintenance of oncogenic transformation. Nature 487, 114–118 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Li, L. et al. SIRT7 is a histone desuccinylase that functionally links to chromatin compaction and genome stability. Nat. Commun. 7, 12235 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Bao, X. C. et al. Identification of 'erasers' for lysine crotonylated histone marks using a chemical proteomics approach. eLife 3, e02999 (2014).

    Article  PubMed Central  Google Scholar 

  53. Scholz, C. et al. Acetylation site specificities of lysine deacetylase inhibitors in human cells. Nat. Biotechnol. 33, 415–423 (2015).

    Article  CAS  PubMed  Google Scholar 

  54. Chen, Y. et al. Quantitative acetylome analysis reveals the roles of SIRT1 in regulating diverse substrates and cellular pathways. Mol. Cell. Proteomics 11, 1048–1062 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Madsen, A. S. & Olsen, C. A. Profiling of substrates for zinc-dependent lysine deacylase enzymes: HDAC3 exhibits decrotonylase activity in vitro. Angew. Chem. Int. Ed. 51, 9083–9087 (2012).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  57. 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 

  58. Moriniere, J. et al. Cooperative binding of two acetylation marks on a histone tail by a single bromodomain. Nature 461, 664–668 (2009).

    Article  CAS  PubMed  Google Scholar 

  59. Goudarzi, A. et al. Dynamic competing histone H4 K5K8 acetylation and butyrylation are hallmarks of highly active gene promoters. Mol. Cell 62, 169–180 (2016). This study demonstrates that dynamic competition between histone Kac and Kbu modulates the binding of BRDT, which in turn controls gene expression and chromatin reorganization during mouse spermatogenesis.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Li, Y. 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 

  61. 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 

  62. Schulze, J. M., Wang, A. Y. & Kobor, M. S. YEATS domain proteins: a diverse family with many links to chromatin modification and transcription. Biochem. Cell Biol. 87, 65–75 (2009).

    Article  CAS  PubMed  Google Scholar 

  63. 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 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. 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 

  66. Zhang, Q. et al. Structural Insights into histone crotonyl-lysine recognition by the AF9 YEATS domain. Structure 24, 1606–1612 (2016). References 63–66 identified the YEATS domain as a histone Kcr-specific reader.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  67. 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 

  68. Li, H. T. 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 

  69. Shi, X. B. 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 

  70. Pena, 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 

  71. 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 

  72. 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 

  73. 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 

  74. 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 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Xiong, X. et al. Selective recognition of histone crotonylation by double PHD fingers of MOZ and DPF2. Nat. Chem. Biol. http://dx.doi.org/10.1038/nchembio.2218 (2016).

  77. Wellen, K. E. et al. ATP–citrate lyase links cellular metabolism to histone acetylation. Science 324, 1076–1080 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Bhanu, N. A.-S., L. & Garcia, B. A. Quantification of lysine crotonylation during in vitro human myogenic differentiation. The 61st Annu. Am. Soc. Mass Spectrom. Conference Mass Spectrom. Allied Top. https://www.abstracts.asms.org/pages/dashboard.html#/conference/253/toc/253/details (2013).

    Google Scholar 

  79. Tweedie-Cullen, R. Y. et al. Identification of combinatorial patterns of post-translational modifications on individual histones in the mouse brain. PLoS ONE 7, e36980 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Comerford, S. A. et al. Acetate dependence of tumors. Cell 159, 1591–1602 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Mashimo, T. et al. Acetate is a bioenergetic substrate for human glioblastoma and brain metastases. Cell 159, 1603–1614 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Hallows, W. C., Lee, S. & Denu, J. M. Sirtuins deacetylate and activate mammalian acetyl-CoA synthetases. Proc. Natl Acad. Sci. USA 103, 10230–10235 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Wellen, K. E. & Thompson, C. B. A two-way street: reciprocal regulation of metabolism and signalling. Nat. Rev. Mol. Cell Biol. 13, 270–276 (2012).

    Article  CAS  PubMed  Google Scholar 

  84. Cahill, G. F. Jr. Fuel metabolism in starvation. Annu. Rev. Nutr. 26, 1–22 (2006).

    Article  CAS  PubMed  Google Scholar 

  85. Robinson, A. M. & Williamson, D. H. Physiological roles of ketone-bodies as substrates and signals in mammalian-tissues. Physiol. Rev. 60, 143–187 (1980).

    Article  CAS  PubMed  Google Scholar 

  86. Lee, J. V. et al. Akt-dependent metabolic reprogramming regulates tumor cell histone acetylation. Cell Metab. 20, 306–319 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Ruiz-Andres, O. et al. Histone lysine crotonylation during acute kidney injury in mice. Dis. Model. Mech. 9, 633–645 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Gaucher, J. et al. Bromodomain-dependent stage-specific male genome programming by Brdt. EMBO J. 31, 3809–3820 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. An, W., Palhan, V. B., Karymov, M. A., Leuba, S. H. & Roeder, R. G. Selective requirements for histone H3 and H4 N termini in p300-dependent transcriptional activation from chromatin. Mol. Cell 9, 811–821 (2002).

    Article  CAS  PubMed  Google Scholar 

  90. Kundu, T. K. et al. Activator-dependent transcription from chromatin in vitro involving targeted histone acetylation by p300. Mol. Cell 6, 551–561 (2000).

    Article  CAS  PubMed  Google Scholar 

  91. Hilton, I. B. et al. Epigenome editing by a CRISPR−Cas9-based acetyltransferase activates genes from promoters and enhancers. Nat. Biotechnol. 33, 510–517 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Smale, S. T., Tarakhovsky, A. & Natoli, G. Chromatin contributions to the regulation of innate immunity. Annu. Rev. Immunol. 32, 489–511 (2014).

    Article  CAS  PubMed  Google Scholar 

  93. Sin, H. S. et al. RNF8 regulates active epigenetic modifications and escape gene activation from inactive sex chromosomes in post-meiotic spermatids. Genes Dev. 26, 2737–2748 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. 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 

  95. Rousseaux, S. & Khochbin, S. Histone acylation beyond acetylation: terra incognita in chromatin biology. Cell J. 17, 1–6 (2015).

    PubMed  PubMed Central  Google Scholar 

  96. McNally, M. A. & Hartman, A. L. Ketone bodies in epilepsy. J. Neurochem. 121, 28–35 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Kashiwaya, Y. et al. D-β-hydroxybutyrate protects neurons in models of Alzheimer's and Parkinson's disease. Proc. Natl Acad. Sci. USA 97, 5440–5444 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Lim, S. et al. D-β-hydroxybutyrate is protective in mouse models of Huntington's disease. PLoS ONE 6, e24620 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Shimazu, T. et al. Suppression of oxidative stress by β-hydroxybutyrate, an endogenous histone deacetylase inhibitor. Science 339, 211–214 (2013).

    Article  CAS  PubMed  Google Scholar 

  100. Boukouris, A. E., Zervopoulos, S. D. & Michelakis, E. D. Metabolic enzymes moonlighting in the nucleus: metabolic regulation of gene transcription. Trends Biochem. Sci. 41, 712–730 (2016).

    Article  CAS  PubMed  Google Scholar 

  101. Yang, X. J. & Seto, E. The Rpd3/Hda1 family of lysine deacetylases: from bacteria and yeast to mice and men. Nat. Rev. Mol. Cell Biol. 9, 206–218 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Legube, G. & Trouche, D. Regulating histone acetyltransferases and deacetylases. EMBO Rep. 4, 944–947 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Tsuchiya, Y., Pham, U. & Gout, I. Methods for measuring CoA and CoA derivatives in biological samples. Biochem. Soc. Trans. 42, 1107–1111 (2014).

    Article  CAS  PubMed  Google Scholar 

  104. Liu, X. et al. High-resolution metabolomics with acyl-CoA profiling reveals widespread remodeling in response to diet. Mol. Cell. Proteomics 14, 1489–1500 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Koh, A., De Vadder, F., Kovatcheva-Datchary, P. & Backhed, F. From dietary fiber to host physiology: short-chain fatty acids as key bacterial metabolites. Cell 165, 1332–1345 (2016).

    Article  CAS  PubMed  Google Scholar 

  106. Lin, H., Su, X. & He, B. Protein lysine acylation and cysteine succination by intermediates of energy metabolism. ACS Chem. Biol. 7, 947–960 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors thank H. Huang, S. Khochbin and members of the Allis laboratory for comments and scientific input. This work was funded by support from The Rockefeller University and from the US National Cancer Institute (CA204639 to C.D.A.), the US National Institutes of Health (NIH) (GM105933, DK107868 and GM115961 to Y.Z.) and the US National Science Foundation (NSF) Graduate Research Fellowship Program (DGE-1325261 to B.R.S).

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  1. Benjamin R. Sabari and Di Zhang: These authors contributed equally to this work.

Authors and Affiliations

  1. Laboratory of Chromatin Biology and Epigenetics, The Rockefeller University, New York, 10065, New York, USA

    Benjamin R. Sabari & C. David Allis

  2. Ben May Department of Cancer Research, The University of Chicago, Chicago, 60637, Illinois, USA

    Di Zhang & Yingming Zhao

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  1. Benjamin R. Sabari
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Correspondence to C. David Allis or Yingming Zhao.

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FURTHER INFORMATION

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OMIM

RSCB Protein Data Bank

Glossary

Short-chain Lys acylations

The addition of a short-chain acyl group (less than six carbon atoms) other than a formyl or acetyl group to the ε-amine of a Lys residue.

Lys acetylation

(Kac). The addition of an acetyl group to the ε-amine of a Lys residue.

ε-Amine

The amino group on the side chain of Lys, where most post-translational modifications occur.

Mass-tolerant database search

An algorithm that allows an unbiased way to search unexplained mass spectrometry data and detect a mass shift at a specific amino acid.

van der Waals interactions

Refers to the attraction between molecules that is not generated from covalent bonds or ionic interactions.

C–C π-bond

A covalent chemical bond that is formed when two atomic orbitals overlap side-to-side along a plane perpendicular to a line that connects the nuclei of the atoms.

Zn2+-dependent histone deacetylases

(Zn2+-dependent HDACs). Classes I, II and IV HDACs that require zinc ions to remove acetyl groups from the ε-amine of Lys residues on histones.

Long-chain acylations

Here refers to Lys acylations with longer hydrocarbon chains such as Lys myristoylation and palmitoylation.

Bromodomain

A protein module of ∼ 110 amino acids that mediates interaction with acetylated Lys and is often found in acetyltransferases and ATP-dependent chromatin remodelling factors.

Isothermal titration calorimetry

A technique to analyse intermolecular interactions by directly measuring the heat generated or absorbed when molecules interact.

Cell-free transcription assays

An in vitro system for RNA synthesis that comprises a reconstituted chromatin template and recombinant transcription factors and cofactors incubated with nuclear extracts.

Histone-to-protamine transition

The process during spermatogenesis in which histones are gradually replaced by Arg-rich protamine, which allows the chromatin in sperm to be tightly packaged.

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Sabari, B., Zhang, D., Allis, C. et al. Metabolic regulation of gene expression through histone acylations. Nat Rev Mol Cell Biol 18, 90–101 (2017). https://doi.org/10.1038/nrm.2016.140

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