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:

EPIGENETICS

Chromatin accessibility and the regulatory epigenome

Nature Reviews Genetics volume 20, pages 207–220 (2019)Cite this article

Subjects

Abstract

Physical access to DNA is a highly dynamic property of chromatin that plays an essential role in establishing and maintaining cellular identity. The organization of accessible chromatin across the genome reflects a network of permissible physical interactions through which enhancers, promoters, insulators and chromatin-binding factors cooperatively regulate gene expression. This landscape of accessibility changes dynamically in response to both external stimuli and developmental cues, and emerging evidence suggests that homeostatic maintenance of accessibility is itself dynamically regulated through a competitive interplay between chromatin-binding factors and nucleosomes. In this Review, we examine how the accessible genome is measured and explore the role of transcription factors in initiating accessibility remodelling; our goal is to illustrate how chromatin accessibility defines regulatory elements within the genome and how these epigenetic features are dynamically established to control gene expression.

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: A continuum of accessibility states broadly reflects the distribution of chromatin dynamics across the genome.
Fig. 2: Principal methods for measuring chromatin accessibility.
Fig. 3: Population-scale measurements of chromatin accessibility reflect the average accessibility of a heterogeneous collection of single molecules.
Fig. 4: Nucleosome turnover and occupancy are inversely correlated across a broad range of genomic regions.
Fig. 5: Models of chromatin accessibility remodelling.

Similar content being viewed by others

References

  1. Kossel, A. Ueber einen peptoartigen bestandheil des zellkerns [German]. Z. Physiol. Chem. 5, 511–515 (1884).

    Google Scholar 

  2. Kossel, A. 1910 Nobel lecture: the chemical composition of the cell nucleus. NobelPrize https://www.nobelprize.org/prizes/medicine/1910/kossel/lecture (2018).

  3. Kornberg, R. D. & Thomas, J. O. Chromatin structure; oligomers of the histones. Science 184, 865–868 (1974).

    Article  CAS  PubMed  Google Scholar 

  4. Kaplan, N. et al. The DNA-encoded nucleosome organization of a eukaryotic genome. Nature 458, 362–366 (2009).

    Article  CAS  PubMed  Google Scholar 

  5. Lorch, Y., LaPointe, J. W. & Kornberg, R. D. Nucleosomes inhibit the initiation of transcription but allow chain elongation with the displacement of histones. Cell 49, 203–210 (1987).

    Article  CAS  PubMed  Google Scholar 

  6. Luger, K., Mäder, A. W., Richmond, R. K., Sargent, D. F. & Richmond, T. J. Crystal structure of the nucleosome core particle at 2.8 Å resolution. Nature 389, 251–260 (1997).

    Article  CAS  PubMed  Google Scholar 

  7. Olins, A. L. & Olins, D. E. Spheroid chromatin units (v bodies). Science 183, 330–332 (1974).

    Article  CAS  PubMed  Google Scholar 

  8. Woodcock, C. L., Safer, J. P. & Stanchfield, J. E. Structural repeating units in chromatin. I. Evidence for their general occurrence. Exp. Cell Res. 97, 101–110 (1976).

    Article  CAS  PubMed  Google Scholar 

  9. Olins, D. E. & Olins, A. L. Chromatin history: our view from the bridge. Nat. Rev. Mol. Cell Biol. 4, 809–814 (2003).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  11. Dann, G. P. et al. ISWI chromatin remodellers sense nucleosome modifications to determine substrate preference. Nature 548, 607–611 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Lee, C.-K., Shibata, Y., Rao, B., Strahl, B. D. & Lieb, J. D. Evidence for nucleosome depletion at active regulatory regions genome-wide. Nat. Genet. 36, 900–905 (2004).

    Article  CAS  PubMed  Google Scholar 

  13. Thurman, R. E. et al. The accessible chromatin landscape of the human genome. Nature 489, 75–82 (2012). This study maps DNase hypersensitivity across 125 human cell lines, demonstrates a strong correlation between distal regulatory elements and promoters and establishes chromatin accessibility as a reliable proxy for cumulative TF binding.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. McBryant, S. J., Adams, V. H. & Hansen, J. C. Chromatin architectural proteins. Chromosome Res. 14, 39–51 (2006).

    Article  CAS  PubMed  Google Scholar 

  15. Bednar, J. et al. Nucleosomes, linker DNA, and linker histone form a unique structural motif that directs the higher-order folding and compaction of chromatin. Proc. Natl Acad. Sci. USA 95, 14173–14178 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Fyodorov, D. V., Zhou, B.-R., Skoultchi, A. I. & Bai, Y. Emerging roles of linker histones in regulating chromatin structure and function. Nat. Rev. Mol. Cell Biol. 19, 192–206 (2018).

    Article  CAS  PubMed  Google Scholar 

  17. Nalabothula, N. et al. The chromatin architectural proteins HMGD1 and H1 bind reciprocally and have opposite effects on chromatin structure and gene regulation. BMC Genomics 15, 92 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  18. Kim, J.-M. et al. Linker histone H1.2 establishes chromatin compaction and gene silencing through recognition of H3K27me3. Sci. Rep. 5, 16714 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Routh, A., Sandin, S. & Rhodes, D. Nucleosome repeat length and linker histone stoichiometry determine chromatin fiber structure. Proc. Natl Acad. Sci. USA 105, 8872–8877 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Izzo, A. et al. Dynamic changes in H1 subtype composition during epigenetic reprogramming. J. Cell Biol. 216, 3017–3028 (2017).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  21. Izzo, A. & Schneider, R. H1 gets the genome in shape. Genome Biol. 17, 8 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. Poirier, M. G., Bussiek, M., Langowski, J. & Widom, J. Spontaneous access to DNA target sites in folded chromatin fibers. J. Mol. Biol. 379, 772–786 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Krebs, A. R. et al. Genome-wide single-molecule footprinting reveals high RNA polymerase II turnover at paused promoters. Mol. Cell 67, 411–422 (2017). This study develops a high-coverage, single-molecule protection assay to show that RNA polymerase II binding is highly dynamic at many gene promoters.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Felsenfeld, G., Boyes, J., Chung, J., Clark, D. & Studitsky, V. Chromatin structure and gene expression. Proc. Natl Acad. Sci. USA 93, 9384–9388 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. John, S. et al. Chromatin accessibility pre-determines glucocorticoid receptor binding patterns. Nat. Genet. 43, 264–268 (2011). This is the first paper to establish that the glucocorticoid receptor almost exclusively binds to open chromatin.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Di Stefano, B. et al. C/EBPα creates elite cells for iPSC reprogramming by upregulating Klf4 and increasing the levels of Lsd1 and Brd4. Nat. Cell Biol. 18, 371–381 (2016). This work shows that the initial epigenetic state of a cell — including chromatin accessibility — determines its reprogramming potential.

    Article  PubMed  CAS  Google Scholar 

  27. Barozzi, I. et al. Coregulation of transcription factor binding and nucleosome occupancy through DNA features of mammalian enhancers. Mol. Cell 54, 844–857 (2014). This paper shows that nucleosome occupancy regulates pioneer factor (PU.1) binding in vivo.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Grøntved, L. et al. C/EBP maintains chromatin accessibility in liver and facilitates glucocorticoid receptor recruitment to steroid response elements. EMBO J. 32, 1568–1583 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. Buenrostro, J. D., Giresi, P. G., Zaba, L. C., Chang, H. Y. & Greenleaf, W. J. Transposition of native chromatin for fast and sensitive epigenomic profiling of open chromatin, DNA-binding proteins and nucleosome position. Nat. Methods 10, 1213–1218 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Corces, M. R. et al. Lineage-specific and single-cell chromatin accessibility charts human hematopoiesis and leukemia evolution. Nat. Genet. 48, 1193–1203 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Buenrostro, J. D. et al. Single-cell chromatin accessibility reveals principles of regulatory variation. Nature 523, 486–490 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Cusanovich, D. A. et al. Multiplex single cell profiling of chromatin accessibility by combinatorial cellular indexing. Science 348, 910–914 (2015). References 31 and 32 are the first reports of single-cell chromatin accessibility.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Corces, M. R. et al. An improved ATAC-seq protocol reduces background and enables interrogation of frozen tissues. Nat. Methods 14, 959–962 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Pott, S. Simultaneous measurement of chromatin accessibility, DNA methylation, and nucleosome phasing in single cells. eLife 6, e23203 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  35. Jin, W. et al. Genome-wide detection of DNase I hypersensitive sites in single cells and FFPE tissue samples. Nature 528, 142–146 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Hewish, D. R. & Burgoyne, L. A. Chromatin sub-structure. The digestion of chromatin DNA at regularly spaced sites by a nuclear deoxyribonuclease. Biochem. Biophys. Res. Commun. 52, 504–510 (1973).

    Article  CAS  PubMed  Google Scholar 

  37. Wu, C., Bingham, P. M., Livak, K. J., Holmgren, R. & Elgin, S. C. The chromatin structure of specific genes: I. Evidence for higher order domains of defined DNA sequence. Cell 16, 797–806 (1979).

    Article  CAS  PubMed  Google Scholar 

  38. Kornberg, R. D. Chromatin structure: a repeating unit of histones and DNA. Science 184, 868–871 (1974).

    Article  CAS  PubMed  Google Scholar 

  39. Wu, C., Wong, Y. C. & Elgin, S. C. The chromatin structure of specific genes: II. Disruption of chromatin structure during gene activity. Cell 16, 807–814 (1979).

    Article  CAS  PubMed  Google Scholar 

  40. Saiki, R. K. et al. Enzymatic amplification of beta-globin genomic sequences and restriction site analysis for diagnosis of sickle cell anemia. Science 230, 1350–1354 (1985).

    Article  CAS  PubMed  Google Scholar 

  41. Mueller, P. R. & Wold, B. In vivo footprinting of a muscle specific enhancer by ligation mediated PCR. Science 246, 780–786 (1989).

    Article  CAS  PubMed  Google Scholar 

  42. Rao, S., Procko, E. & Shannon, M. F. Chromatin remodeling, measured by a novel real-time polymerase chain reaction assay, across the proximal promoter region of the IL-2 gene. J. Immunol. 167, 4494–4503 (2001).

    Article  CAS  PubMed  Google Scholar 

  43. Crawford, G. E. et al. DNase-chip: a high-resolution method to identify DNase I hypersensitive sites using tiled microarrays. Nat. Methods 3, 503–509 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Sabo, P. J. et al. Genome-scale mapping of DNase I sensitivity in vivo using tiling DNA microarrays. Nat. Methods 3, 511–518 (2006). References 43 and 44 provide the first genome-wide measurements of DNase hypersensitivity.

    Article  CAS  PubMed  Google Scholar 

  45. Boyle, A. P. et al. High-resolution mapping and characterization of open chromatin across the genome. Cell 132, 311–322 (2008). As the first genome-wide sequencing measurement of DNase hypersensitivity (DNase-seq), this paper establishes widespread distal regulatory accessibility at gene enhancers and periodic accessibility along nucleosomal DNA.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Hesselberth, J. R. et al. Global mapping of protein-DNA interactions in vivo by digital genomic footprinting. Nat. Methods 6, 283–289 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. John, S. et al. Interaction of the glucocorticoid receptor with the chromatin landscape. Mol. Cell 29, 611–624 (2008).

    Article  CAS  PubMed  Google Scholar 

  48. Baek, S., Goldstein, I. & Hager, G. L. Bivariate genomic footprinting detects changes in transcription factor activity. Cell Rep. 19, 1710–1722 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Schwessinger, R. et al. Sasquatch: predicting the impact of regulatory SNPs on transcription factor binding from cell- and tissue-specific DNase footprints. Genome Res. 27, 1730–1742 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Sos, B. C. et al. Characterization of chromatin accessibility with a transposome hypersensitive sites sequencing (THS-seq) assay. Genome Biol. 17, 20 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  51. He, H. H. et al. Refined DNase-seq protocol and data analysis reveals intrinsic bias in transcription factor footprint identification. Nat. Methods 11, 73–78 (2014).

    Article  CAS  PubMed  Google Scholar 

  52. Schep, A. N. et al. Structured nucleosome fingerprints enable high-resolution mapping of chromatin architecture within regulatory regions. Genome Res. 25, 1757–1770 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Meyer, C. A. & Liu, X. S. Identifying and mitigating bias in next-generation sequencing methods for chromatin biology. Nat. Rev. Genet. 15, 709–721 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Buenrostro, J. D., Wu, B., Chang, H. Y. & Greenleaf, W. J. ATAC-seq: a method for assaying chromatin accessibility genome-wide. Curr. Protoc. Mol. Biol. 109, 21.29.1–21.29.9 (2015).

    Article  Google Scholar 

  55. Mieczkowski, J. et al. MNase titration reveals differences between nucleosome occupancy and chromatin accessibility. Nat. Commun. 7, 11485 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Mueller, B. et al. Widespread changes in nucleosome accessibility without changes in nucleosome occupancy during a rapid transcriptional induction. Genes Dev. 31, 451–462 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Allan, J., Fraser, R. M., Owen-Hughes, T. & Keszenman-Pereyra, D. Micrococcal nuclease does not substantially bias nucleosome mapping. J. Mol. Biol. 417, 152–164 (2012).

    Article  CAS  PubMed  Google Scholar 

  58. Lorzadeh, A. et al. Nucleosome density ChIP-seq identifies distinct chromatin modification signatures associated with MNase accessibility. Cell Rep. 17, 2112–2124 (2016).

    Article  CAS  PubMed  Google Scholar 

  59. Chung, H.-R. et al. The effect of micrococcal nuclease digestion on nucleosome positioning data. PLOS ONE 5, e15754 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Teif, V. B. et al. Nucleosome repositioning links DNA (de)methylation and differential CTCF binding during stem cell development. Genome Res. 24, 1285–1295 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Kelly, T. K. et al. Genome-wide mapping of nucleosome positioning and DNA methylation within individual DNA molecules. Genome Res. 22, 2497–2506 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Cusanovich, D. A. et al. The cis-regulatory dynamics of embryonic development at single-cell resolution. Nature 555, 538–542 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Cusanovich, D. A. et al. A single-cell atlas of in vivo mammalian chromatin accessibility. Cell 174, 1309–1324 (2018). Together, references 62 and 63 map the epigenetics of organismal development using an ultrahigh-throughput single-cell ATAC-seq assay.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Preissl, S. et al. Single-nucleus analysis of accessible chromatin in developing mouse forebrain reveals cell-type-specific transcriptional regulation. Nat. Neurosci. 21, 432–439 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Mezger, A. et al. High-throughput chromatin accessibility profiling at single-cell resolution. Nat. Commun. 9, 3647 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  66. Clark, S. J. et al. scNMT-seq enables joint profiling of chromatin accessibility DNA methylation and transcription in single cells. Nat. Commun. 9, 781 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  67. Sung, M.-H., Baek, S. & Hager, G. L. Genome-wide footprinting: ready for prime time? Nat. Methods 13, 222–228 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Stergachis, A. B. et al. Conservation of trans-acting circuitry during mammalian regulatory evolution. Nature 515, 365–370 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Denny, S. K. et al. Nfib promotes metastasis through a widespread increase in chromatin accessibility. Cell 166, 328–342 (2016). This paper shows that the metastatic TF NFIB exploits a weakly accessible binding site in primary tumours to initiate oncogenic accessibility remodelling.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Schep, A. N., Wu, B., Buenrostro, J. D. & Greenleaf, W. J. chromVAR: inferring transcription-factor-associated accessibility from single-cell epigenomic data. Nat. Methods 14, 975–978 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Sherwood, R. I. et al. Discovery of directional and nondirectional pioneer transcription factors by modeling DNase profile magnitude and shape. Nat. Biotechnol. 32, 171–178 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Lango Allen, H. et al. Hundreds of variants clustered in genomic loci and biological pathways affect human height. Nature 467, 832–838 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Qu, K. et al. Individuality and variation of personal regulomes in primary human T cells. Cell Syst. 1, 51–61 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Maurano, M. T. et al. Systematic localization of common disease-associated variation in regulatory DNA. Science 337, 1190–1195 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Lareau, C. A. et al. Interrogation of human hematopoiesis at single-cell and single-variant resolution. Preprint at bioRxiv https://www.biorxiv.org/content/early/2018/01/28/255224 (2018).

  76. Deal, R. B., Henikoff, J. G. & Henikoff, S. Genome-wide kinetics of nucleosome turnover determined by metabolic labeling of histones. Science 328, 1161–1164 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Sung, M.-H., Guertin, M. J., Baek, S. & Hager, G. L. DNase footprint signatures are dictated by factor dynamics and DNA sequence. Mol. Cell 56, 275–285 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. He, H. H. et al. Nucleosome dynamics define transcriptional enhancers. Nat. Genet. 42, 343–347 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. El Gazzar, M., Liu, T., Yoza, B. K. & McCall, C. E. Dynamic and selective nucleosome repositioning during endotoxin tolerance. J. Biol. Chem. 285, 1259–1271 (2010).

    Article  CAS  PubMed  Google Scholar 

  80. Schones, D. E. et al. Dynamic regulation of nucleosome positioning in the human genome. Cell 132, 887–898 (2008).

    Article  CAS  PubMed  Google Scholar 

  81. Deaton, A. M. et al. Enhancer regions show high histone H3.3 turnover that changes during differentiation. eLife 5, e15316 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  82. Lever, M. A., Th’ng, J. P., Sun, X. & Hendzel, M. J. Rapid exchange of histone H1.1 on chromatin in living human cells. Nature 408, 873–876 (2000).

    Article  CAS  PubMed  Google Scholar 

  83. Almer, A. & Hörz, W. Nuclease hypersensitive regions with adjacent positioned nucleosomes mark the gene boundaries of the PHO5/PHO3 locus in yeast. EMBO J. 5, 2681–2687 (1986).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Hartley, P. D. & Madhani, H. D. Mechanisms that specify promoter nucleosome location and identity. Cell 137, 445–458 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Yuan, G.-C. et al. Genome-scale identification of nucleosome positions in S. cerevisiae. Science 309, 626–630 (2005).

    Article  CAS  PubMed  Google Scholar 

  86. Segal, E. et al. A genomic code for nucleosome positioning. Nature 442, 772–778 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Voong, L. N. et al. Insights into nucleosome organization in mouse embryonic stem cells through chemical mapping. Cell 167, 1555–1570 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Risca, V. I. & Greenleaf, W. J. Unraveling the 3D genome: genomics tools for multiscale exploration. Trends Genet. 31, 357–372 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Gilchrist, D. A. et al. Pausing of RNA polymerase II disrupts DNA-specified nucleosome organization to enable precise gene regulation. Cell 143, 540–551 (2010). This paper shows that RNA polymerase II pausing increases gene expression at some loci by maintaining a nucleosome-depleted TSS.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Kornberg, R. The location of nucleosomes in chromatin: specific or statistical. Nature 292, 579–580 (1981).

    Article  CAS  PubMed  Google Scholar 

  91. Mavrich, T. N. et al. A barrier nucleosome model for statistical positioning of nucleosomes throughout the yeast genome. Genome Res. 18, 1073–1083 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Riposo, J. & Mozziconacci, J. Nucleosome positioning and nucleosome stacking: two faces of the same coin. Mol. Biosyst. 8, 1172–1178 (2012).

    Article  CAS  PubMed  Google Scholar 

  93. Moyle-Heyrman, G. et al. Chemical map of Schizosaccharomyces pombe reveals species-specific features in nucleosome positioning. Proc. Natl Acad. Sci. USA 110, 20158–20163 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Müller, O. et al. Changing chromatin fiber conformation by nucleosome repositioning. Biophys. J. 107, 2141–2150 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  95. Valouev, A. et al. Determinants of nucleosome organization in primary human cells. Nature 474, 516–520 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Grishkevich, V., Hashimshony, T. & Yanai, I. Core promoter T-blocks correlate with gene expression levels in. C. elegans. Genome Res. 21, 707–717 (2011).

    Article  CAS  PubMed  Google Scholar 

  97. Raveh-Sadka, T. et al. Manipulating nucleosome disfavoring sequences allows fine-tune regulation of gene expression in yeast. Nat. Genet. 44, 743–750 (2012).

    Article  CAS  PubMed  Google Scholar 

  98. Valouev, A. et al. A high-resolution, nucleosome position map of C. elegans reveals a lack of universal sequence-dictated positioning. Genome Res. 18, 1051–1063 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Tillo, D. et al. High nucleosome occupancy is encoded at human regulatory sequences. PLOS ONE 5, e9129 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  100. Creyghton, M. P. et al. H2AZ is enriched at polycomb complex target genes in ES cells and is necessary for lineage commitment. Cell 135, 649–661 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Hu, G. et al. H2A. Z facilitates access of active and repressive complexes to chromatin in embryonic stem cell self-renewal and differentiation. Cell Stem Cell 12, 180–192 (2013).

    Article  CAS  PubMed  Google Scholar 

  102. Wang, Z. et al. Genome-wide mapping of HATs and HDACs reveals distinct functions in active and inactive genes. Cell 138, 1019–1031 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Scharf, A. N. D. et al. Monomethylation of lysine 20 on histone H4 facilitates chromatin maturation. Mol. Cell. Biol. 29, 57–67 (2009).

    Article  CAS  PubMed  Google Scholar 

  104. Fan, Y. et al. Histone H1 depletion in mammals alters global chromatin structure but causes specific changes in gene regulation. Cell 123, 1199–1212 (2005).

    Article  CAS  PubMed  Google Scholar 

  105. Thoma, F., Koller, T. & Klug, A. Involvement of histone H1 in the organization of the nucleosome and of the salt-dependent superstructures of chromatin. J. Cell Biol. 83, 403–427 (1979).

    Article  CAS  PubMed  Google Scholar 

  106. Li, G. & Reinberg, D. Chromatin higher-order structures and gene regulation. Curr. Opin. Genet. Dev. 21, 175–186 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Ricci, M. A., Manzo, C., García-Parajo, M. F., Lakadamyali, M. & Cosma, M. P. Chromatin fibers are formed by heterogeneous groups of nucleosomes in vivo. Cell 160, 1145–1158 (2015).

    Article  CAS  PubMed  Google Scholar 

  108. Zhou, B.-R. et al. Structural mechanisms of nucleosome recognition by linker histones. Mol. Cell 59, 628–638 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Bednar, J. et al. Structure and dynamics of a 197bp nucleosome in complex with linker histone H1. Mol. Cell 66, 384–397 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Patterton, H. G., Landel, C. C., Landsman, D., Peterson, C. L. & Simpson, R. T. The biochemical and phenotypic characterization of Hho1p, the putative linker histone H1 of Saccharomyces cerevisiae. J. Biol. Chem. 273, 7268–7276 (1998).

    Article  CAS  PubMed  Google Scholar 

  111. Ramón, A., Muro-Pastor, M. I., Scazzocchio, C. & Gonzalez, R. Deletion of the unique gene encoding a typical histone H1 has no apparent phenotype in Aspergillus nidulans. Mol. Microbiol. 35, 223–233 (2000).

    Article  PubMed  Google Scholar 

  112. Shen, X. & Gorovsky, M. A. Linker histone H1 regulates specific gene expression but not global transcription in vivo. Cell 86, 475–483 (1996).

    Article  CAS  PubMed  Google Scholar 

  113. Ushinsky, S. C. et al. Histone H1 in Saccharomyces cerevisiae. Yeast 13, 151–161 (1997).

    Article  CAS  PubMed  Google Scholar 

  114. Thomas, J. O. & Stott, K. H1 and HMGB1: modulators of chromatin structure. Biochem. Soc. Trans. 40, 341–346 (2012).

    Article  CAS  PubMed  Google Scholar 

  115. Thomas, J. O. Histone H1: location and role. Curr. Opin. Cell Biol. 11, 312–317 (1999).

    Article  CAS  PubMed  Google Scholar 

  116. Juan, L. J., Utley, R. T., Vignali, M., Bohm, L. & Workman, J. L. H1-mediated repression of transcription factor binding to a stably positioned nucleosome. J. Biol. Chem. 272, 3635–3640 (1997).

    Article  CAS  PubMed  Google Scholar 

  117. Vignali, M. & Workman, J. L. Location and function of linker histones. Nat. Struct. Biol. 5, 1025–1028 (1998).

    Article  CAS  PubMed  Google Scholar 

  118. Torres, C. M. et al. The linker histone H1.0 generates epigenetic and functional intratumor heterogeneity. Science 353, aaf1644 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Machida, S. et al. Structural basis of heterochromatin formation by human HP1. Mol. Cell 69, 385–397 (2018).

    Article  CAS  PubMed  Google Scholar 

  120. Robinson, P. J. J. et al. 30 nm chromatin fibre decompaction requires both H4-K16 acetylation and linker histone eviction. J. Mol. Biol. 381, 816–825 (2008).

    Article  CAS  PubMed  Google Scholar 

  121. Wallrath, L. L. & Elgin, S. C. Position effect variegation in Drosophila is associated with an altered chromatin structure. Genes Dev. 9, 1263–1277 (1995).

    Article  CAS  PubMed  Google Scholar 

  122. Koslover, E. F., Fuller, C. J., Straight, A. F. & Spakowitz, A. J. Local geometry and elasticity in compact chromatin structure. Biophys. J. 99, 3941–3950 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Collepardo-Guevara, R. & Schlick, T. Chromatin fiber polymorphism triggered by variations of DNA linker lengths. Proc. Natl Acad. Sci. USA 111, 8061–8066 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Barbi, M., Mozziconacci, J. & Victor, J.-M. How the chromatin fiber deals with topological constraints. Phys. Rev. E 71, 031910 (2005).

    Article  CAS  Google Scholar 

  125. Nikitina, T., Norouzi, D., Grigoryev, S. A. & Zhurkin, V. B. DNA topology in chromatin is defined by nucleosome spacing. Sci. Adv. 3, e1700957 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  126. Risca, V. I., Denny, S. K., Straight, A. F. & Greenleaf, W. J. Variable chromatin structure revealed by in situ spatially correlated DNA cleavage mapping. Nature 541, 237–241 (2017). This paper shows that nucleosomal packing is heterogeneous across the genome, with more frequent non-adjacent nucleosome contacts in heterochromatin than in euchromatin.

    Article  CAS  PubMed  Google Scholar 

  127. Schalch, T., Duda, S., Sargent, D. F. & Richmond, T. J. X-ray structure of a tetranucleosome and its implications for the chromatin fibre. Nature 436, 138–141 (2005).

    Article  CAS  PubMed  Google Scholar 

  128. Song, F. et al. Cryo-EM study of the chromatin fiber reveals a double helix twisted by tetranucleosomal units. Science 344, 376–380 (2014).

    Article  CAS  PubMed  Google Scholar 

  129. Hsieh, T.-H. S. et al. Mapping nucleosome resolution chromosome folding in yeast by Micro-C. Cell 162, 108–119 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Ou, H. D. et al. ChromEMT: Visualizing 3D chromatin structure and compaction in interphase and mitotic cells. Science 357, eaag0025 (2017). This paper shows that higher-order chromatin organization is heterogeneous across the genome and that chromatin density is the primary distinguishing property of heterochromatin and euchromatin.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  131. Lara-Astiaso, D. et al. Immunogenetics. Chromatin state dynamics during blood formation. Science 345, 943–949 (2014). This paper shows that acquisition of H3K4me1 (a mark commonly observed at poised enhancers) during haematopoiesis is accompanied by an increase in chromatin accessibility.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Saeed, S. et al. Epigenetic programming of monocyte-to-macrophage differentiation and trained innate immunity. Science 345, 1251086 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  133. Svaren, J., Klebanow, E., Sealy, L. & Chalkley, R. Analysis of the competition between nucleosome formation and transcription factor binding. J. Biol. Chem. 269, 9335–9344 (1994).

    CAS  PubMed  Google Scholar 

  134. Workman, J. L. & Kingston, R. E. Nucleosome core displacement in vitro via a metastable transcription factor-nucleosome complex. Science 258, 1780–1784 (1992).

    Article  CAS  PubMed  Google Scholar 

  135. Swinstead, E. E., Paakinaho, V., Presman, D. M. & Hager, G. L. Pioneer factors and ATP-dependent chromatin remodeling factors interact dynamically — a new perspective: Multiple transcription factors can effect chromatin pioneer functions through dynamic interactions with ATP-dependent chromatin remodeling factors. Bioessays 38, 1150–1157 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Bao, X. et al. A novel ATAC-seq approach reveals lineage-specific reinforcement of the open chromatin landscape via cooperation between BAF and p63. Genome Biol. 16, 284 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  137. Gertz, J. et al. Distinct properties of cell-type-specific and shared transcription factor binding sites. Mol. Cell 52, 25–36 (2013).

    Article  CAS  PubMed  Google Scholar 

  138. Commerford, S. L., Carsten, A. L. & Cronkite, E. P. Histone turnover within nonproliferating cells. Proc. Natl Acad. Sci. USA 79, 1163–1165 (1982).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Mirny, L. A. Nucleosome-mediated cooperativity between transcription factors. Proc. Natl Acad. Sci. USA 107, 22534–22539 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Miller, J. A. & Widom, J. Collaborative competition mechanism for gene activation in vivo. Mol. Cell. Biol. 23, 1623–1632 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Ramachandran, S. & Henikoff, S. Transcriptional regulators compete with nucleosomes post-replication. Cell 165, 580–592 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Amodeo, A. A., Jukam, D., Straight, A. F. & Skotheim, J. M. Histone titration against the genome sets the DNA-to-cytoplasm threshold for the Xenopus midblastula transition. Proc. Natl Acad. Sci. USA 112, E1086–E1095 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Joseph, S. R. et al. Competition between histone and transcription factor binding regulates the onset of transcription in zebrafish embryos. eLife 6, e23326 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  144. Gómez-Díaz, E. & Corces, V. G. Architectural proteins: regulators of 3D genome organization in cell fate. Trends Cell Biol. 24, 703–711 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  145. Ramakrishnan, V. Histone structure and the organization of the nucleosome. Annu. Rev. Biophys. Biomol. Struct. 26, 83–112 (1997).

    Article  CAS  PubMed  Google Scholar 

  146. Ramakrishnan, V. Histone H1 and chromatin higher-order structure. Crit. Rev. Eukaryot. Gene Expr 7, 215–230 (1997).

    Article  CAS  PubMed  Google Scholar 

  147. Lone, I. N. et al. Binding of NF-κB to nucleosomes: effect of translational positioning, nucleosome remodeling and linker histone H1. PLOS Genet. 9, e1003830 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Steger, D. J. & Workman, J. L. Stable co-occupancy of transcription factors and histones at the HIV-1 enhancer. EMBO J. 16, 2463–2472 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Cirillo, L. A. et al. Opening of compacted chromatin by early developmental transcription factors HNF3 (FoxA) and GATA-4. Mol. Cell 9, 279–289 (2002).

    Article  CAS  PubMed  Google Scholar 

  150. Glass, C. K. & Natoli, G. Molecular control of activation and priming in macrophages. Nat. Immunol. 17, 26–33 (2016).

    Article  CAS  PubMed  Google Scholar 

  151. Natoli, G. Control of NF-kappaB-dependent transcriptional responses by chromatin organization. Cold Spring Harb. Perspect. Biol. 1, a000224 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  152. Vicent, G. P. et al. Four enzymes cooperate to displace histone H1 during the first minute of hormonal gene activation. Genes Dev. 25, 845–862 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Taberlay, P. C. et al. Polycomb-repressed genes have permissive enhancers that initiate reprogramming. Cell 147, 1283–1294 (2011). This paper introduces the NOMe-seq chromatin accessibility assay and shows that TF binding to a distal enhancer can facilitate cellular reprogramming by remodelling promoter-proximal accessibility in trans.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Almer, A., Rudolph, H., Hinnen, A. & Hörz, W. Removal of positioned nucleosomes from the yeast PHO5 promoter upon PHO5 induction releases additional upstream activating DNA elements. EMBO J. 5, 2689–2696 (1986).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Taylor, I. C., Workman, J. L., Schuetz, T. J. & Kingston, R. E. Facilitated binding of GAL4 and heat shock factor to nucleosomal templates: differential function of DNA-binding domains. Genes Dev. 5, 1285–1298 (1991).

    Article  CAS  PubMed  Google Scholar 

  156. McPherson, C. E., Shim, E. Y., Friedman, D. S. & Zaret, K. S. An active tissue-specific enhancer and bound transcription factors existing in a precisely positioned nucleosomal array. Cell 75, 387–398 (1993).

    Article  CAS  PubMed  Google Scholar 

  157. Zaret, K. S. & Carroll, J. S. Pioneer transcription factors: establishing competence for gene expression. Genes Dev. 25, 2227–2241 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Soufi, A. et al. Pioneer transcription factors target partial DNA motifs on nucleosomes to initiate reprogramming. Cell 161, 555–568 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Zaret, K. S. Pioneering the chromatin landscape. Nat. Genet. 50, 167–169 (2018).

    Article  CAS  PubMed  Google Scholar 

  160. Soufi, A., Donahue, G. & Zaret, K. S. Facilitators and impediments of the pluripotency reprogramming factors’ initial engagement with the genome. Cell 151, 994–1004 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Iwafuchi-Doi, M. et al. The pioneer transcription factor FoxA maintains an accessible nucleosome configuration at enhancers for tissue-specific gene activation. Mol. Cell 62, 79–91 (2016). This paper shows that the pioneer TF FOXA displaces histone H1 in murine liver.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Donaghey, J. et al. Genetic determinants and epigenetic effects of pioneer-factor occupancy. Nat. Genet. 50, 250–258 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Clark, D. J. & Felsenfeld, G. A nucleosome core is transferred out of the path of a transcribing polymerase. Cell 71, 11–22 (1992).

    Article  CAS  PubMed  Google Scholar 

  164. Clark, D. et al. Chromatin structure of transcriptionally active genes. Cold Spring Harb. Symp. Quant. Biol. 58, 1–6 (1993).

    Article  CAS  PubMed  Google Scholar 

  165. Nagai, S., Davis, R. E., Mattei, P. J., Eagen, K. P. & Kornberg, R. D. Chromatin potentiates transcription. Proc. Natl Acad. Sci. USA 114, 1536–1541 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Li, B., Carey, M. & Workman, J. L. The role of chromatin during transcription. Cell 128, 707–719 (2007).

    Article  CAS  PubMed  Google Scholar 

  167. Dogan, N. et al. Occupancy by key transcription factors is a more accurate predictor of enhancer activity than histone modifications or chromatin accessibility. Epigenetics Chromatin 8, 16 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  168. Heinz, S., Romanoski, C. E., Benner, C. & Glass, C. K. The selection and function of cell type-specific enhancers. Nat. Rev. Mol. Cell Biol. 16, 144–154 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Barski, A. et al. High-resolution profiling of histone methylations in the human genome. Cell 129, 823–837 (2007).

    Article  CAS  PubMed  Google Scholar 

  170. Schulz, K. N. et al. Zelda is differentially required for chromatin accessibility, transcription factor binding, and gene expression in the early Drosophila embryo. Genome Res. 25, 1715–1726 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. Mognol, G. P. et al. Exhaustion-associated regulatory regions in CD8+tumor-infiltrating T cells. Proc. Natl Acad. Sci. USA 114, E2776–E2785 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Amit, I. & Winter, D. R. The role of chromatin dynamics in immune cell development. Immunol. Rev. 261, 9–122 (2014).

    Article  PubMed  CAS  Google Scholar 

  173. Pereira, R. M., Hogan, P. G., Rao, A. & Martinez, G. J. Transcriptional and epigenetic regulation of T cell hyporesponsiveness. J. Leukoc. Biol. 102, 601–615 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Scott-Browne, J. P. et al. Dynamic changes in chromatin accessibility occur in CD8 + T cells responding to viral infection. Immunity 45, 1327–1340 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. Qu, K. et al. Chromatin accessibility landscape of cutaneous T cell lymphoma and dynamic response to HDAC inhibitors. Cancer Cell 32, 27–41 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  176. Satpathy, A. T. et al. Transcript-indexed ATAC-seq for precision immune profiling. Nat. Med. 24, 580–590 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. Cao, J. et al. Joint profiling of chromatin accessibility and gene expression in thousands of single cells. Science 361, 1380–1385 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors thank M. Moria-Shipony for graphics assistance as well as A. Koh, V. Risca, G. Marinov, N. Sinnott-Armstrong and A. Trevino for critical feedback on this manuscript. This work was supported by the NIH (P50HG007735, UM1HG009442, U19AI057266 and 1UM1HG009436), the Rita Allen Foundation, the Baxter Foundation Faculty Scholar Grant and the Human Frontiers Science Program grant RGY006S. W.J.G is a Chan Zuckerberg Biohub investigator and acknowledges grants 2017-174468 and 2018-182817 from the Chan Zuckerberg Initiative. Z.S. is supported by grants EMBO ALTF 1119-2016 and HFSP LT 000835/2017-L. S.K. has received support from a Ruth L. Kirschstein Institutional National Research Service Award (NRSA, NIH 5 T32 HG000044).

Reviewer information

Nature Reviews Genetics thanks D. Gifford, K. Rippe and the other, anonymous reviewer(s) for their contribution to the peer review of this work.

Author information

Author notes

  1. These authors contributed equally: Sandy L. Klemm, Zohar Shipony.

Authors and Affiliations

  1. Department of Genetics, Stanford University, Stanford, CA, USA

    Sandy L. Klemm, Zohar Shipony & William J. Greenleaf

  2. Department of Applied Physics, Stanford University, Stanford, CA, USA

    William J. Greenleaf

  3. Chan Zuckerberg BioHub, San Francisco, CA, USA

    William J. Greenleaf

Authors
  1. Sandy L. Klemm
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Zohar Shipony
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. William J. Greenleaf
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

S.L.K., Z.S. and W.J.G. conceived and wrote the manuscript.

Corresponding author

Correspondence to William J. Greenleaf.

Ethics declarations

Competing interests

W.J.G. is a co-founder of Epinomics and an adviser to 10X Genomics, Guardant Health and Centrillion.

Additional information

Publisher’s note

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

Related links

10X Genomics single-cell ATAC-seq: https://www.10xgenomics.com/solutions/single-cell-atac/

Bio-Rad Laboratories single-cell ATAC-seq: http://www.bio-rad.com/scATAC-Seq

Glossary

Chromatin-binding factors

Non-histone macromolecules that bind either directly or indirectly to DNA.

Transcription factor

(TF). A non-histone protein that directly binds to DNA.

Architectural proteins

Proteins that have a structural role in organizing chromatin, including linker and core histone proteins, as well as insulator proteins.

Nucleosome occupancy

The fraction of time that a particular sequence of DNA is bound by the core histone octamer.

Epigenetic canalization

A set of persistent epigenetic features (alternatively, the process of establishing this feature set) that molecularly defines a cell type and comprises a continuum of cellular states including cell cycle phases and activation states.

TF footprinting

High-resolution analysis of chromatin accessibility data to identify a local accessibility signature in the neighbourhood of putative binding sites for a particular transcription factor (TF). This signature reflects the size and binding mechanism, as well as other biophysical properties, of a TF.

Nucleosome turnover rates

The rates at which nucleosomes disassemble at particular genomic loci; alternatively, the inverse of the nucleosome residence times.

Poised enhancers

Inactive enhancers that do not regulate gene expression but share a subset of epigenetic features commonly observed at active enhancers, including histone H3 lysine 4 monomethylation (H3K4me)and accessibility.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Klemm, S.L., Shipony, Z. & Greenleaf, W.J. Chromatin accessibility and the regulatory epigenome. Nat Rev Genet 20, 207–220 (2019). https://doi.org/10.1038/s41576-018-0089-8

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41576-018-0089-8

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