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.

  • Review Article
  • Published:

Epigenetic regulation of the innate immune response to infection

Nature Reviews Immunology volume 19, pages 417–432 (2019)Cite this article

Subjects

Abstract

Innate immune cells have complex signalling pathways for sensing pathogens and initiating innate immune responses against infection. These pathways are tightly regulated at different levels, including by epigenetic regulators. In this Review, we discuss studies revealing the epigenetic mechanisms, as well as the post-transcriptional and post-translational modifications by chromatin modifiers, that underlie the establishment of these signalling networks and the rapid induction of innate immune molecules during infection. We also discuss how pathogens use their own products, as well as host components, to target host epigenomes for immune evasion and survival. We describe the crosstalk between epigenetic regulators and new modulators, such as inflammation-specific metabolites, and how we might deconstruct dynamic chromatin patterns and identify critical chromatin modifiers of host–pathogen interactions.

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

Fig. 1: Interplay between epigenetic regulation and innate immunity against infection.
Fig. 2: Epigenetic regulation of signalling pathways during infection.
Fig. 3: Epigenetic regulation of effector molecules that act against infection.
Fig. 4: Crosstalk between cell metabolic pathways and epigenetic regulation in innate immunity.
Fig. 5: Pathogen products directly and indirectly regulate the host epigenome.

Similar content being viewed by others

References

  1. Medzhitov, R. Toll-like receptors and innate immunity. Nat. Rev. Immunol. 1, 135–145 (2001).

    Article  CAS  PubMed  Google Scholar 

  2. Cao, X. Self-regulation and cross-regulation of pattern-recognition receptor signalling in health and disease. Nat. Rev. Immunol. 16, 35–50 (2016).

    Article  CAS  PubMed  Google Scholar 

  3. Brown, G. D., Willment, J. A. & Whitehead, L. C-type lectins in immunity and homeostasis. Nat. Rev. Immunol. 18, 374–389 (2018).

    Article  CAS  PubMed  Google Scholar 

  4. Bird, A. Perceptions of epigenetics. Nature 447, 396–398 (2007).

    Article  CAS  PubMed  Google Scholar 

  5. Allis, C. D. & Jenuwein, T. The molecular hallmarks of epigenetic control. Nat. Rev. Genet. 17, 487–500 (2016).

    Article  CAS  PubMed  Google Scholar 

  6. Wu, X. & Zhang, Y. TET-mediated active DNA demethylation: mechanism, function and beyond. Nat. Rev. Genet. 18, 517–534 (2017).

    Article  CAS  PubMed  Google Scholar 

  7. Jones, P. A. Functions of DNA methylation: islands, start sites, gene bodies and beyond. Nat. Rev. Genet. 13, 484–492 (2012).

    Article  CAS  PubMed  Google Scholar 

  8. Tahiliani, M. et al. Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1. Science 324, 930–935 (2009). This is the first study to reveal that TET proteins can catalyse 5mC oxidation, indicating a critical role of TET proteins in DNA methylation regulation.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Heyn, H. & Esteller, M. An adenine code for DNA: a second life for N6-methyladenine. Cell 161, 710–713 (2015).

    Article  CAS  PubMed  Google Scholar 

  10. Wu, T. P. et al. DNA methylation on N(6)-adenine in mammalian embryonic stem cells. Nature 532, 329–333 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Brownell, J. E. et al. Tetrahymena histone acetyltransferase A: a homolog to yeast Gcn5p linking histone acetylation to gene activation. Cell 84, 843–851 (1996). In this study, the authors identify a first histone acetyltransferase, known as Gcn5 in yeast, revealing a potential role of histone modification in regulating gene expression.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  13. Andrews, F. H., Strahl, B. D. & Kutateladze, T. G. Insights into newly discovered marks and readers of epigenetic information. Nat. Chem. Biol. 12, 662–668 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Clapier, C. R., Iwasa, J., Cairns, B. R. & Peterson, C. L. Mechanisms of action and regulation of ATP-dependent chromatin-remodelling complexes. Nat. Rev. Mol. Cell. Biol. 18, 407–422 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Quinn, J. J. & Chang, H. Y. Unique features of long non-coding RNA biogenesis and function. Nat. Rev. Genet. 17, 47–62 (2016).

    CAS  PubMed  Google Scholar 

  16. Brockdorff, N. Noncoding RNA and polycomb recruitment. RNA 19, 429–442 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Chen, Y. G., Satpathy, A. T. & Chang, H. Y. Gene regulation in the immune system by long noncoding RNAs. Nat. Immunol. 18, 962–972 (2017).

    Article  CAS  PubMed  Google Scholar 

  18. Zhang, Y. & Cao, X. Long noncoding RNAs in innate immunity. Cell. Mol. Immunol. 13, 138–147 (2016).

    Article  PubMed  CAS  Google Scholar 

  19. Jia, G. et al. N6-methyladenosine in nuclear RNA is a major substrate of the obesity-associated FTO. Nat. Chem. Biol. 7, 885–887 (2011). This work reports the first m6A RNA demethylase FTO, highlighting the biological function of reversible m6A in mRNAs.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Roundtree, I. A., Evans, M. E., Pan, T. & He, C. Dynamic RNA modifications in gene expression regulation. Cell 169, 1187–1200 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Liddicoat, B. J. et al. RNA editing by ADAR1 prevents MDA5 sensing of endogenous dsRNA as nonself. Science 349, 1115–1120 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Chung, H. et al. Human ADAR1 prevents endogenous RNA from triggering translational shutdown. Cell 172, 811–824 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Schwartzman, O. & Tanay, A. Single-cell epigenomics: techniques and emerging applications. Nat. Rev. Genet. 16, 716–726 (2015).

    Article  CAS  PubMed  Google Scholar 

  24. Shema, E. et al. Single-molecule decoding of combinatorially modified nucleosomes. Science 352, 717–721 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Romanoski, C. E., Glass, C. K., Stunnenberg, H. G., Wilson, L. & Almouzni, G. Epigenomics: roadmap for regulation. Nature 518, 314–316 (2015).

    Article  CAS  PubMed  Google Scholar 

  26. Burel, J. G., Apte, S. H. & Doolan, D. L. Systems approaches towards molecular profiling of human Immunity. Trends Immunol. 37, 53–67 (2016).

    Article  CAS  PubMed  Google Scholar 

  27. Heng, T. S. & Painter, M. W. The Immunological Genome Project: networks of gene expression in immune cells. Nat. Immunol. 9, 1091–1094 (2008).

    Article  CAS  PubMed  Google Scholar 

  28. Austenaa, L. et al. The histone methyltransferase Wbp7 controls macrophage function through GPI glycolipid anchor synthesis. Immunity 36, 572–585 (2012). This publication shows that H3K4me3 is involved in regulating the TLR4 signalling pathway and establishes genome-wide profiles of H3K4me3 in macrophages during the LPS response.

    Article  CAS  PubMed  Google Scholar 

  29. Liu, Y. et al. Histone lysine methyltransferase Ezh1 promotes TLR-triggered inflammatory cytokine production by suppressing Tollip. J. Immunol. 194, 2838–2846 (2015).

    Article  CAS  PubMed  Google Scholar 

  30. Li, Xia, et al. Methyltransferase Dnmt3a upregulates HDAC9 to deacetylate the kinase TBK1 for activation of antiviral innate immunity. Nat. Immunol. 17, 806–815 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Zhao, D. et al. H3K4me3 demethylase Kdm5a is required for NK cell activation by associating with p50 to suppress SOCS1. Cell Rep. 15, 288–299 (2016).

    Article  CAS  PubMed  Google Scholar 

  32. Xia, M. et al. Histone methyltransferase Ash1l suppresses interleukin-6 production and inflammatory autoimmune diseases by inducing the ubiquitin-editing enzyme A20. Immunity 39, 470–481 (2013).

    Article  CAS  PubMed  Google Scholar 

  33. Zheng, Q., Hou, J., Zhou, Y., Li, Z. & Cao, X. The RNA helicase DDX46 inhibits innate immunity by entrapping m(6)A-demethylated antiviral transcripts in the nucleus. Nat. Immunol. 18, 1094–1103 (2017).

    Article  CAS  PubMed  Google Scholar 

  34. Shen, Q. et al. Tet2 promotes pathogen infection-induced myelopoiesis through mRNA oxidation. Nature 554, 123–127 (2018).

    Article  CAS  PubMed  Google Scholar 

  35. Li, T., Diner, B. A., Chen, J. & Cristea, I. M. Acetylation modulates cellular distribution and DNA sensing ability of interferon-inducible protein IFI16. Proc. Natl Acad. Sci. USA 109, 10558–10563 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Xia, P. et al. Glutamylation of the DNA sensor cGAS regulates its binding and synthase activity in antiviral immunity. Nat. Immunol. 17, 369–378 (2016).

    Article  CAS  PubMed  Google Scholar 

  37. Li, T. et al. O-GlcNAc transferase links glucose metabolism to MAVS-mediated antiviral innate immunity. Cell Host Microbe 24, 791–803 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Chen, L., Fischle, W., Verdin, E. & Greene, W. C. Duration of nuclear NF-kappaB action regulated by reversible acetylation. Science 293, 1653–1657 (2001).

    Article  CAS  Google Scholar 

  39. Kiernan, R. et al. Post-activation turn-off of NF-kappa B-dependent transcription is regulated by acetylation of p65. J. Biol. Chem. 278, 2758–2766 (2003).

    Article  CAS  PubMed  Google Scholar 

  40. Lu, T. & Stark, G. R. NF-kappaB: regulation by methylation. Cancer Res. 75, 3692–3695 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Lu, T. et al. Regulation of NF-kappaB by NSD1/FBXL11-dependent reversible lysine methylation of p65. Proc. Natl Acad. Sci. USA 107, 46–51 (2010).

    Article  CAS  PubMed  Google Scholar 

  42. Kim, D. et al. PKCalpha-LSD1-NF-kappaB-signaling cascade is crucial for epigenetic control of the inflammatory response. Mol. Cell 69, 398–411 (2018).

    Article  CAS  PubMed  Google Scholar 

  43. Chen, K. et al. Methyltransferase SETD2-mediated methylation of STAT1 is critical for interferon antiviral activity. Cell 170, 492–506 (2017). This study reveals the role of non-histone lysine methylation involved in regulating the antiviral signalling pathway.

    Article  CAS  PubMed  Google Scholar 

  44. Wang, C. et al. The methyltransferase NSD3 promotes antiviral innate immunity via direct lysine methylation of IRF3. J. Exp. Med. 214, 3597–3610 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Suhara, W., Yoneyama, M., Kitabayashi, I. & Fujita, T. Direct involvement of CREB-binding protein/p300 in sequence-specific DNA binding of virus-activated interferon regulatory factor-3 holocomplex. J. Biol. Chem. 277, 22304–22313 (2002).

    Article  CAS  PubMed  Google Scholar 

  46. Chiang, J. J. et al. Viral unmasking of cellular 5S rRNA pseudogene transcripts induces RIG-I-mediated immunity. Nat. Immunol. 19, 53–62 (2018).

    Article  CAS  PubMed  Google Scholar 

  47. Jiang, M. et al. Self-recognition of an inducible host lncRNA by RIG-I feedback restricts innate immune response. Cell 173, 906–919 (2018).

    Article  CAS  PubMed  Google Scholar 

  48. Chen, Y. G. et al. Sensing self and foreign circular RNAs by intron identity. Mol. Cell 67, 228–238 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Ramirez-Carrozzi, V. R. et al. Selective and antagonistic functions of SWI/SNF and Mi-2beta nucleosome remodeling complexes during an inflammatory response. Genes Dev. 20, 282–296 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Ramirez-Carrozzi, V. R. et al. A unifying model for the selective regulation of inducible transcription by CpG islands and nucleosome remodeling. Cell 138, 114–128 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Hargreaves, D. C., Horng, T. & Medzhitov, R. Control of inducible gene expression by signal-dependent transcriptional elongation. Cell 138, 129–145 (2009). Together with Ramirez-Carrozzi et al. (2006, 2009), this study classifies primary and secondary response genes and reveals distinct epigenetic mechanisms involved in establishing distinct transcription patterns between the two gene subsets upon LPS stimulation.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. 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 

  53. Lai, D. et al. Induction of TLR4-target genes entails calcium/calmodulin-dependent regulation of chromatin remodeling. Proc. Natl Acad. Sci. USA 106, 1169–1174 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Tartey, S. et al. Akirin2 is critical for inducing inflammatory genes by bridging IkappaB-zeta and the SWI/SNF complex. EMBO J. 33, 2332–2348 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Rialdi, A. et al. Topoisomerase 1 inhibition suppresses inflammatory genes and protects from death by inflammation. Science 352, aad7993 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  56. Nicodeme, E. et al. Suppression of inflammation by a synthetic histone mimic. Nature 468, 1119–1123 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Sadler, A. J. et al. The acetyltransferase HAT1 moderates the NF-kappaB response by regulating the transcription factor PLZF. Nat. Commun. 6, 6795 (2015).

    Article  CAS  PubMed  Google Scholar 

  58. Meng, J. et al. Rb selectively inhibits innate IFN-beta production by enhancing deacetylation of IFN-beta promoter through HDAC1 and HDAC8. J. Autoimmun. 73, 42–53 (2016).

    Article  CAS  PubMed  Google Scholar 

  59. Xue, S. et al. TET3 inhibits type I IFN production independent of DNA demethylation. Cell Rep. 16, 1096–1105 (2016).

    Article  CAS  PubMed  Google Scholar 

  60. Yao, Z. et al. Death domain-associated protein 6 (Daxx) selectively represses IL-6 transcription through histone deacetylase 1 (HDAC1)-mediated histone deacetylation in macrophages. J. Biol. Chem. 289, 9372–9379 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Kawahara, T. L. et al. SIRT6 links histone H3 lysine 9 deacetylation to NF-kappaB-dependent gene expression and organismal life span. Cell 136, 62–74 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Yan, Q. et al. Nuclear factor-kappaB binding motifs specify Toll-like receptor-induced gene repression through an inducible repressosome. Proc. Natl Acad. Sci. USA 109, 14140–14145 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Zhang, Q. et al. Tet2 is required to resolve inflammation by recruiting Hdac2 to specifically repress IL-6. Nature 525, 389–393 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Shakespear, M. R., Halili, M. A., Irvine, K. M., Fairlie, D. P. & Sweet, M. J. Histone deacetylases as regulators of inflammation and immunity. Trends Immunol. 32, 335–343 (2011).

    Article  CAS  PubMed  Google Scholar 

  65. Tang, X. et al. Acetylation-dependent signal transduction for type I interferon receptor. Cell 131, 93–105 (2007).

    Article  CAS  PubMed  Google Scholar 

  66. Yu, L. et al. MRTF-A mediates LPS-induced pro-inflammatory transcription by interacting with the COMPASS complex. J. Cell Sci. 127, 4645–4657 (2014).

    PubMed  Google Scholar 

  67. Kayama, H. et al. Class-specific regulation of pro-inflammatory genes by MyD88 pathways and IkappaBzeta. J. Biol. Chem. 283, 12468–12477 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Carson, W. F. et al. The STAT4/MLL1 epigenetic axis regulates the antimicrobial functions of murine macrophages. J. Immunol. 199, 1865–1874 (2017).

    Article  CAS  PubMed  Google Scholar 

  69. Song, M. et al. MKL1 is an epigenetic mediator of TNF-alpha-induced proinflammatory transcription in macrophages by interacting with ASH2. FEBS Lett. 591, 934–945 (2017).

    Article  CAS  PubMed  Google Scholar 

  70. Yu, L. et al. MKL1 defines the H3K4Me3 landscape for NF-kappaB dependent inflammatory response. Sci. Rep. 7, 191 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  71. Xu, J. et al. Nuclear carbonic anhydrase 6B associates with PRMT5 to epigenetically promote IL-12 expression in innate response. Proc. Natl Acad. Sci. USA 114, 8620–8625 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Jayne, S., Rothgiesser, K. M. & Hottiger, M. O. CARM1 but not its enzymatic activity is required for transcriptional coactivation of NF-kappaB-dependent gene expression. J. Mol. Biol. 394, 485–495 (2009).

    Article  CAS  PubMed  Google Scholar 

  73. Anest, V. et al. A nucleosomal function for IkappaB kinase-alpha in NF-kappaB-dependent gene expression. Nature 423, 659–663 (2003).

    Article  CAS  PubMed  Google Scholar 

  74. Yamamoto, Y., Verma, U. N., Prajapati, S., Kwak, Y. T. & Gaynor, R. B. Histone H3 phosphorylation by IKK-alpha is critical for cytokine-induced gene expression. Nature 423, 655–659 (2003).

    Article  CAS  PubMed  Google Scholar 

  75. Saccani, S., Pantano, S. & Natoli, G. p38-Dependent marking of inflammatory genes for increased NF-kappa B recruitment. Nat. Immunol. 3, 69–75 (2002). Together with Yamamoto et al. (2003), this study reports that MAPK-dependent H3 phosphorylation is required for induction of subsets of pro-inflammatory genes, revealing nonclassical roles of protein kinases in chromatin regulation.

    Article  CAS  PubMed  Google Scholar 

  76. Josefowicz, S. et al. Targeting chromatin kinases reveals their role in inducible transcription of inflammatory genes. J. Immunol. 196 (Suppl. 1), 202.13 (2016).

    Google Scholar 

  77. Reintjes, A. et al. Asymmetric arginine dimethylation of RelA provides a repressive mark to modulate TNFalpha/NF-kappaB response. Proc. Natl Acad. Sci. USA 113, 4326–4331 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Wei, H. et al. PRMT5 dimethylates R30 of the p65 subunit to activate NF-kappaB. Proc. Natl Acad. Sci. USA 110, 13516–13521 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Hoberg, J. E., Popko, A. E., Ramsey, C. S. & Mayo, M. W. IkappaB kinase alpha-mediated derepression of SMRT potentiates acetylation of RelA/p65 by p300. Mol. Cell. Biol. 26, 457–471 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Jin, J. et al. Noncanonical NF-kappaB pathway controls the production of type I interferons in antiviral innate immunity. Immunity 40, 342–354 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Zhu, Y., van Essen, D. & Saccani, S. Cell-type-specific control of enhancer activity by H3K9 trimethylation. Mol. Cell 46, 408–423 (2012).

    Article  CAS  PubMed  Google Scholar 

  82. van Essen, D., Zhu, Y. & Saccani, S. A feed-forward circuit controlling inducible NF-kappaB target gene activation by promoter histone demethylation. Mol. Cell 39, 750–760 (2010).

    Article  PubMed  CAS  Google Scholar 

  83. Fang, T. C. et al. Histone H3 lysine 9 di-methylation as an epigenetic signature of the interferon response. J. Exp. Med. 209, 661–669 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Stender, J. D. et al. Control of proinflammatory gene programs by regulated trimethylation and demethylation of histone H4K20. Mol. Cell 48, 28–38 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Kruidenier, L. et al. A selective jumonji H3K27 demethylase inhibitor modulates the proinflammatory macrophage response. Nature 488, 404–408 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Li, X. et al. Demethylase Kdm6a epigenetically promotes IL-6 and IFN-beta production in macrophages. J. Autoimmun. 80, 85–94 (2017).

    Article  CAS  PubMed  Google Scholar 

  87. Tarcic, O. et al. RNF20 links histone H2B ubiquitylation with inflammation and inflammation-associated cancer. Cell Rep. 14, 1462–1476 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Zhou, W. et al. Histone H2A monoubiquitination represses transcription by inhibiting RNA polymerase II transcriptional elongation. Mol. Cell 29, 69–80 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  89. Zhong, H., May, M. J., Jimi, E. & Ghosh, S. The phosphorylation status of nuclear NF-kappa B determines its association with CBP/p300 or HDAC-1. Mol. Cell 9, 625–636 (2002).

    Article  CAS  PubMed  Google Scholar 

  90. Atianand, M. K., Caffrey, D. R. & Fitzgerald, K. A. Immunobiology of long noncoding RNAs. Annu. Rev. Immunol. 35, 177–198 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Carpenter, S. et al. A long noncoding RNA mediates both activation and repression of immune response genes. Science 341, 789–792 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Atianand, M. K. et al. A long noncoding RNA lincRNA-EPS acts as a transcriptional brake to restrain inflammation. Cell 165, 1672–1685 (2016). Together with Carpenter et al. (2013), this study reveals that two TLR-signal regulated nuclear lncRNAs act with RNA-binding proteins to modulate the transcription of subsets of innate immune response genes.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Kaikkonen, M. U. et al. Remodeling of the enhancer landscape during macrophage activation is coupled to enhancer transcription. Mol. Cell 51, 310–325 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Qiao, Y. et al. Synergistic activation of inflammatory cytokine genes by interferon-gamma-induced chromatin remodeling and toll-like receptor signaling. Immunity 39, 454–469 (2013).

    Article  CAS  PubMed  Google Scholar 

  95. Decque, A. et al. Sumoylation coordinates the repression of inflammatory and anti-viral gene-expression programs during innate sensing. Nat. Immunol. 17, 140–149 (2016).

    Article  CAS  PubMed  Google Scholar 

  96. Czimmerer, Z. et al. The transcription factor STAT6 mediates direct repression of inflammatory enhancers and limits activation of alternatively polarized macrophages. Immunity 48, 75–90 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Hah, N. et al. Inflammation-sensitive super enhancers form domains of coordinately regulated enhancer RNAs. Proc. Natl Acad. Sci. USA 112, E297–E302 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Li, Z. et al. Exon-intron circular RNAs regulate transcription in the nucleus. Nat. Struct. Mol. Biol. 22, 256–264 (2015).

    Article  PubMed  CAS  Google Scholar 

  99. Yin, Q. F. et al. Long noncoding RNAs with snoRNA ends. Mol. Cell 48, 219–230 (2012).

    Article  CAS  PubMed  Google Scholar 

  100. Ganeshan, K. & Chawla, A. Metabolic regulation of immune responses. Annu. Rev. Immunol. 32, 609–634 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. 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 

  102. Tannahill, G. M. et al. Succinate is an inflammatory signal that induces IL-1beta through HIF-1alpha. Nature 496, 238–242 (2013). This work reports that M1 activation triggers the Warburg effect and identifies succinate as a pro-inflammatory metabolite that promotes transcription of IL-1β.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Palsson-McDermott, E. M. et al. Pyruvate kinase M2 regulates HIF-1alpha activity and IL-1beta induction and is a critical determinant of the Warburg effect in LPS-activated macrophages. Cell Metab. 21, 347 (2015).

    Article  CAS  PubMed  Google Scholar 

  104. Liu, P. S. et al. alpha-Ketoglutarate orchestrates macrophage activation through metabolic and epigenetic reprogramming. Nat. Immunol. 18, 985–994 (2017).

    Article  CAS  PubMed  Google Scholar 

  105. Hardbower, D. M. et al. Ornithine decarboxylase regulates M1 macrophage activation and mucosal inflammation via histone modifications. Proc. Natl Acad. Sci. USA 114, E751–E760 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Shen, Y. et al. Bioenergetic state regulates innate inflammatory responses through the transcriptional co-repressor CtBP. Nat. Commun. 8, 624 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  107. Yeung, F. et al. Modulation of NF-kappaB-dependent transcription and cell survival by the SIRT1 deacetylase. EMBO J. 23, 2369–2380 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Misawa, T. et al. Microtubule-driven spatial arrangement of mitochondria promotes activation of the NLRP3 inflammasome. Nat. Immunol. 14, 454–460 (2013).

    Article  CAS  PubMed  Google Scholar 

  109. Lin, J., Handschin, C. & Spiegelman, B. M. Metabolic control through the PGC-1 family of transcription coactivators. Cell Metab. 1, 361–370 (2005).

    Article  PubMed  CAS  Google Scholar 

  110. Mills, E. L. et al. Itaconate is an anti-inflammatory metabolite that activates Nrf2 via alkylation of KEAP1. Nature 556, 113–117 (2018). This publication demonstrates that the metabolite itaconate inhibits inflammation through activation of NRF2 via alkylation of the NRF2-specific repressor KEAP1, providing a novel mechanism of metabolite-mediated regulation.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Bambouskova, M. et al. Electrophilic properties of itaconate and derivatives regulate the IkappaBzeta-ATF3 inflammatory axis. Nature 556, 501–504 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Ost, A. & Pospisilik, J. A. Epigenetic modulation of metabolic decisions. Curr. Opin. Cell Biol. 33, 88–94 (2015).

    Article  PubMed  CAS  Google Scholar 

  113. Wang, P., Xu, J., Wang, Y. & Cao, X. An interferon-independent lncRNA promotes viral replication by modulating cellular metabolism. Science 358, 1051–1055 (2017). This study identifies a cytoplasmic lncRNA that binds to the metabolic enzyme GOT2 and regulates its activity to promote viral replication.

    Article  CAS  PubMed  Google Scholar 

  114. Netea, M. G. et al. Trained immunity: a program of innate immune memory in health and disease. Science 352, aaf1098 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  115. Foster, S. L., Hargreaves, D. C. & Medzhitov, R. Gene-specific control of inflammation by TLR-induced chromatin modifications. Nature 447, 972–978 (2007).

    Article  CAS  PubMed  Google Scholar 

  116. Novakovic, B. et al. beta-Glucan reverses the epigenetic state of LPS-induced immunological tolerance. Cell 167, 1354–1368 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Chen, J. & Ivashkiv, L. B. IFN-gamma abrogates endotoxin tolerance by facilitating Toll-like receptor-induced chromatin remodeling. Proc. Natl Acad. Sci. USA 107, 19438–19443 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Quintin, J. et al. Candida albicans infection affords protection against reinfection via functional reprogramming of monocytes. Cell Host Microbe 12, 223–232 (2012).

    Article  CAS  PubMed  Google Scholar 

  119. Saeed, S. et al. Epigenetic programming of monocyte-to-macrophage differentiation and trained innate immunity. Science 345, 1251086 (2014). This work connects the molecular mechanisms of both tolerant and trained innate immunity to epigenetic regulation in an epigenomic view.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  120. Kaufmann, E. et al. BCG educates hematopoietic stem cells to generate protective innate immunity against tuberculosis. Cell 172, 176–190 (2018).

    Article  CAS  PubMed  Google Scholar 

  121. Mitroulis, I. et al. Modulation of myelopoiesis progenitors is an integral component of trained immunity. Cell 172, 147–161 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Dominguez-Andres, J. et al. The itaconate pathway is a central regulatory node linking innate immune tolerance and trained immunity. Cell Metab. 29, 211–220 (2018).

    Article  PubMed  CAS  Google Scholar 

  123. Cheng, S. C. et al. mTOR- and HIF-1alpha-mediated aerobic glycolysis as metabolic basis for trained immunity. Science 345, 1250684 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  124. Arts, R. J. et al. Glutaminolysis and fumarate accumulation integrate immunometabolic and epigenetic programs in trained immunity. Cell Metab. 24, 807–819 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Bekkering, S. et al. Metabolic induction of trained immunity through the mevalonate pathway. Cell 172, 135–146 (2018).

    Article  CAS  PubMed  Google Scholar 

  126. Paschos, K. & Allday, M. J. Epigenetic reprogramming of host genes in viral and microbial pathogenesis. Trends Microbiol. 18, 439–447 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Tsai, C. L. et al. Activation of DNA methyltransferase 1 by EBV LMP1 involves c-Jun NH(2)-terminal kinase signaling. Cancer Res. 66, 11668–11676 (2006).

    Article  CAS  PubMed  Google Scholar 

  128. Hino, R. et al. Activation of DNA methyltransferase 1 by EBV latent membrane protein 2A leads to promoter hypermethylation of PTEN gene in gastric carcinoma. Cancer Res. 69, 2766–2774 (2009).

    Article  CAS  PubMed  Google Scholar 

  129. Periyasamy, P. et al. Epigenetic promoter DNA methylation of miR-124 promotes HIV-1 Tat-mediated microglial activation via MECP2-STAT3 axis. J. Neurosci. 38, 5367–5383 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Pion, M., Jaramillo-Ruiz, D., Martinez, A., Munoz-Fernandez, M. A. & Correa-Rocha, R. HIV infection of human regulatory T cells downregulates Foxp3 expression by increasing DNMT3b levels and DNA methylation in the FOXP3 gene. AIDS 27, 2019–2029 (2013).

    Article  CAS  PubMed  Google Scholar 

  131. Youngblood, B. et al. Cutting edge: prolonged exposure to HIV reinforces a poised epigenetic program for PD-1 expression in virus-specific CD8 T cells. J. Immunol. 191, 540–544 (2013).

    Article  CAS  PubMed  Google Scholar 

  132. Namba-Fukuyo, H. et al. TET2 functions as a resistance factor against DNA methylation acquisition during Epstein-Barr virus infection. Oncotarget 7, 81512–81526 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  133. Gokhale, N. S. & Horner, S. M. RNA modifications go viral. PLOS Pathog. 13, e1006188 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  134. Ptaschinski, C. et al. RSV-induced H3K4 demethylase KDM5B leads to regulation of dendritic cell-derived innate cytokines and exacerbates pathogenesis in vivo. PLOS Pathog. 11, e1004978 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  135. Zheng, D. L. et al. Epigenetic modification induced by hepatitis B virus X protein via interaction with de novo DNA methyltransferase DNMT3A. J. Hepatol. 50, 377–387 (2009).

    Article  CAS  PubMed  Google Scholar 

  136. Lu, F. et al. Identification of host-chromosome binding sites and candidate gene targets for Kaposi’s sarcoma-associated herpesvirus LANA. J. Virol. 86, 5752–5762 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Ferrari, R. et al. Epigenetic reprogramming by adenovirus e1a. Science 321, 1086–1088 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Ferrari, R. et al. Adenovirus small E1A employs the lysine acetylases p300/CBP and tumor suppressor Rb to repress select host genes and promote productive virus infection. Cell Host Microbe 16, 663–676 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Fonseca, G. J. et al. Adenovirus evasion of interferon-mediated innate immunity by direct antagonism of a cellular histone posttranslational modification. Cell Host Microbe 11, 597–606 (2012).

    Article  CAS  PubMed  Google Scholar 

  140. Rossetto, C. C. & Pari, G. S. Kaposi’s sarcoma-associated herpesvirus noncoding polyadenylated nuclear RNA interacts with virus- and host cell-encoded proteins and suppresses expression of genes involved in immune modulation. J. Virol. 85, 13290–13297 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Rossetto, C. C., Tarrant-Elorza, M., Verma, S., Purushothaman, P. & Pari, G. S. Regulation of viral and cellular gene expression by Kaposi’s sarcoma-associated herpesvirus polyadenylated nuclear RNA. J. Virol. 87, 5540–5553 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Schliehe, C. et al. The methyltransferase Setdb2 mediates virus-induced susceptibility to bacterial superinfection. Nat. Immunol. 16, 67–74 (2015).

    Article  CAS  PubMed  Google Scholar 

  143. Yang, J., Tian, B., Sun, H., Garofalo, R. P. & Brasier, A. R. Epigenetic silencing of IRF1 dysregulates type III interferon responses to respiratory virus infection in epithelial to mesenchymal transition. Nat. Microbiol. 2, 17086 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Russell, A. B., Peterson, S. B. & Mougous, J. D. Type VI secretion system effectors: poisons with a purpose. Nat. Rev. Microbiol. 12, 137–148 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Bierne, H., Hamon, M. & Cossart, P. Epigenetics and bacterial infections. Cold Spring Harb. Perspect. Med. 2, a010272 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  146. Escoll, P., Mondino, S., Rolando, M. & Buchrieser, C. Targeting of host organelles by pathogenic bacteria: a sophisticated subversion strategy. Nat. Rev. Microbiol. 14, 5–19 (2016).

    Article  CAS  PubMed  Google Scholar 

  147. Eskandarian, H. A. et al. A role for SIRT2-dependent histone H3K18 deacetylation in bacterial infection. Science 341, 1238858 (2013). This is a representative work that demonstrates how pathogen products modulate the transcription of pro-inflammatory genes through regulating host epigenetic regulators.

    Article  PubMed  CAS  Google Scholar 

  148. Singh, V. et al. Histone methyltransferase SET8 epigenetically reprograms host immune responses to assist mycobacterial survival. J. Infect. Dis. 216, 477–488 (2017).

    Article  CAS  PubMed  Google Scholar 

  149. Yaseen, I., Kaur, P., Nandicoori, V. K. & Khosla, S. Mycobacteria modulate host epigenetic machinery by Rv1988 methylation of a non-tail arginine of histone H3. Nat. Commun. 6, 8922 (2015).

    Article  CAS  PubMed  Google Scholar 

  150. Wang, J. et al. The mycobacterial phosphatase PtpA regulates the expression of host genes and promotes cell proliferation. Nat. Commun. 8, 244 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  151. Satoh, T. et al. The Jmjd3-Irf4 axis regulates M2 macrophage polarization and host responses against helminth infection. Nat. Immunol. 11, 936–944 (2010).

    Article  CAS  PubMed  Google Scholar 

  152. Mullican, S. E. et al. Histone deacetylase 3 is an epigenomic brake in macrophage alternative activation. Genes Dev. 25, 2480–2488 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Robert McMaster, W., Morrison, C. J. & Kobor, M. S. Epigenetics: a new model for intracellular parasite-host cell regulation. Trends Parasitol. 32, 515–521 (2016).

    Article  CAS  PubMed  Google Scholar 

  154. Marr, A. K. et al. Leishmania donovani infection causes distinct epigenetic DNA methylation changes in host macrophages. PLOS Pathog. 10, e1004419 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  155. Bougdour, A. et al. Host cell subversion by Toxoplasma GRA16, an exported dense granule protein that targets the host cell nucleus and alters gene expression. Cell Host Microbe 13, 489–500 (2013).

    Article  CAS  PubMed  Google Scholar 

  156. Alvarez, Y. et al. Sirtuin 1 is a key regulator of the interleukin-12 p70/interleukin-23 balance in human dendritic cells. J. Biol. Chem. 287, 35689–35701 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Meisel, M. et al. Microbial signals drive pre-leukaemic myeloproliferation in a Tet2-deficient host. Nature 557, 580–584 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Jostins, L. et al. Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature 491, 119–124 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Franke, A. et al. Genome-wide meta-analysis increases to 71 the number of confirmed Crohn’s disease susceptibility loci. Nat. Genet. 42, 1118–1125 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Zhang, Z. & Zhang, R. Epigenetics in autoimmune diseases: pathogenesis and prospects for therapy. Autoimmun. Rev. 14, 854–863 (2015).

    Article  CAS  PubMed  Google Scholar 

  161. Klein, K. & Gay, S. Epigenetics in rheumatoid arthritis. Curr. Opin. Rheumatol. 27, 76–82 (2015).

    Article  CAS  PubMed  Google Scholar 

  162. Jeffries, M. A. Epigenetic editing: how cutting-edge targeted epigenetic modification might provide novel avenues for autoimmune disease therapy. Clin. Immunol. 196, 49–58 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Plongthongkum, N., Diep, D. H. & Zhang, K. Advances in the profiling of DNA modifications: cytosine methylation and beyond. Nat. Rev. Genet. 15, 647–661 (2014).

    Article  CAS  PubMed  Google Scholar 

  164. Teschendorff, A.E. & Relton, C.L. Statistical and integrative system-level analysis of DNA methylation data. Nat. Rev. Genet. 19, 129–147 (2018).

    Article  CAS  PubMed  Google Scholar 

  165. Henning, A. N., Roychoudhuri, R. & Restifo, N. P. Epigenetic control of CD8+ T cell differentiation. Nat. Rev. Immunol. 18, 340–356 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Stricker, S. H., Koferle, A. & Beck, S. From profiles to function in epigenomics. Nat. Rev. Genet. 18, 51–66 (2017).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by grants from the National Natural Science Foundation of China (81788101) and Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences (2016-I2M-1-003).

Reviewer information

Nature Reviews Immunology thanks S.-C. Sun and other anonymous reviewer(s) for their contribution to the peer review of this work.

Author information

Authors and Affiliations

  1. College of Life Science, Nankai University, Tianjin, China

    Qian Zhang & Xuetao Cao

  2. National Key Laboratory of Medical Immunology & Institute of Immunology, Second Military Medical University, Shanghai, China

    Qian Zhang & Xuetao Cao

  3. Department of Immunology & Center for Immunotherapy, Institute of Basic Medical Sciences, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China

    Xuetao Cao

Authors
  1. Qian Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xuetao Cao
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

The authors contributed equally to all aspects of the article.

Corresponding authors

Correspondence to Qian Zhang or Xuetao Cao.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Glossary

CpG islands

(CGIs). Genomic regions of more than 500 nucleotides in length with higher-than-average frequency (surpasses 0.6) of CG dinucleotide bases. They are often associated with the transcription start sites of genes and are also found in gene bodies and intergenic regions. The DNA methylation status of these regions regulates genomic structures and gene transcription.

Readers

Proteins that specifically recognize modified DNA, RNA or proteins via special protein domains.

Long non-coding RNAs

Transcripts, longer than 200 nucleotides, that resemble protein-coding mRNAs in that they are capped, spliced and polyadenylated RNA polymerase II transcripts, but they lack a protein-coding open reading frame. They can act in cis or in trans to sequester (decoy) or recruit (guide) regulators from their targets or assemble large complexes (scaffold).

Competing endogenous RNAs

(ceRNAs). Long non-coding RNAs that regulate other RNA transcripts by competing for shared microRNAs.

Enhancer RNAs

(eRNAs). Long non-coding RNAs that are transcribed from active enhancer elements.

Circular RNAs

(circRNAs). Long non-coding RNAs that form a covalently closed RNA loop with the 3΄ and 5΄ ends joined together, acting as sponges for microRNAs.

Writers

Enzymes that add specific modifications to DNA, RNA or proteins.

Erasers

Enzymes that remove specific modifications from DNA, RNA or proteins.

Primary response genes

(PRGs). Genes that are rapidly induced by lipopolysaccharide simply by post-translational activation of transcription factors and are mostly independent of chromatin remodelling.

Secondary response genes

(SRGs). Genes whose induction by lipopolysaccharide requires newly synthesized proteins during the primary response and depend on chromatin remodelling.

RNA Pol II transcriptional elongation

During gene transcription, after RNA polymerase II (RNA Pol II) binds the promoter and initiates DNA transcription, a transcription elongation factor such as P-TEFb mediates productive elongation to generate full-length properly processed mRNAs.

COMPASS complex

A conserved protein complex that catalyses methylation of histone H3. Originally identified as the first H3K4 methylase in yeast, in which it is associated with a trithorax-related SET domain protein. In mammals, it contains a catalytic subunit (SETD1A or SETD1B) and other members such as ASH2L and KMT2A.

Histone code

Post-translational modifications of histone proteins that regulate the accessibility of chromatin-bound DNA to the general transcription machinery to provide an instructive code for cell-specific and tissue-specific gene expression.

Super-enhancers

A genomic region containing a group of putative enhancers in close genomic proximity with unusually high levels of transcription factor and mediator co-activator binding that enhances gene transcription.

M1 and M2 macrophages

‘M1’ and ‘M2’ are classifications historically used to define macrophages activated in vitro as pro-inflammatory (when classically activated with interferon-γ (IFNγ) and lipopolysaccharide (LPS)) or anti-inflammatory (when alternatively activated with IL-4 or IL-10), respectively. However, in vivo macrophages are highly specialized, transcriptomically dynamic and extremely heterogeneous with regard to their phenotypes and functions, which are continuously shaped by their tissue microenvironment. Therefore, the M1 or M2 classification is too simplistic to explain the true nature of in vivo macrophages, although these terms are still often used to indicate whether the macrophages in question are more pro-inflammatory or anti-inflammatory.

Warburg effect

The phenomenon in which inflammatory and cancer cells demonstrate a shift in energy metabolism away from oxidative phosphorylation (which is dominant in resting cells) towards aerobic glycolysis, thereby making them able to more rapidly provide ATP and metabolic intermediates for the biosynthesis of immune and inflammatory proteins.

Tricarboxylic acid cycle

(TCA cycle). Also known as the citric acid cycle or Krebs cycle. This cycle is a series of enzymatic reactions used in aerobic metabolism to release energy through the oxidation of acetyl-CoA to yield ATP and carbon dioxide.

Superinfection

A second infection superimposed on an earlier one, especially by a different kind of pathogen.

SET domain

Suvar3–9, enhancer-of-zeste, trithorax domain. An evolutionarily conserved sequence motif that was initially identified in Drosophila melanogaster. It is present in many histone methyltransferases and is required for methylation of histones and non-histone targets.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhang, Q., Cao, X. Epigenetic regulation of the innate immune response to infection. Nat Rev Immunol 19, 417–432 (2019). https://doi.org/10.1038/s41577-019-0151-6

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41577-019-0151-6

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