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.

Genomic regulation of transcription and RNA processing by the multitasking Integrator complex

Abstract

In higher eukaryotes, fine-tuned activation of protein-coding genes and many non-coding RNAs pivots around the regulated activity of RNA polymerase II (Pol II). The Integrator complex is the only Pol II-associated large multiprotein complex that is metazoan specific, and has therefore been understudied for years. Integrator comprises at least 14 subunits, which are grouped into distinct functional modules. The phosphodiesterase activity of the core catalytic module is co-transcriptionally directed against several RNA species, including long non-coding RNAs (lncRNAs), U small nuclear RNAs (U snRNAs), PIWI-interacting RNAs (piRNAs), enhancer RNAs and nascent pre-mRNAs. Processing of non-coding RNAs by Integrator is essential for their biogenesis, and at protein-coding genes, Integrator is a key modulator of Pol II promoter-proximal pausing and transcript elongation. Recent studies have identified an Integrator-specific serine/threonine-protein phosphatase 2A (PP2A) module, which targets Pol II and other components of the basal transcription machinery. In this Review, we discuss how the activity of Integrator regulates transcription, RNA processing, chromatin landscape and DNA repair. We also discuss the diverse roles of Integrator in development and tumorigenesis.

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

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Fig. 1: Subunits of the mammalian Integrator complex.
Fig. 2: Structural features and assembly of Integrator.
Fig. 3: Integrator terminates transcription of non-coding RNAs.
Fig. 4: Cleavage of nascent pre-mRNA at RNA polymerase II pausing sites.
Fig. 5: Integrator with the phosphatase module inhibits pause release of RNA polymerase II.

References

  1. Roeder, R. G. & Rutter, W. J. Multiple forms of DNA-dependent RNA polymerase in eukaryotic organisms. Nature 224, 234–237 (1969).

    Article  CAS  PubMed  Google Scholar 

  2. Young, R. A. RNA polymerase II. Annu. Rev. Biochem. 60, 689–715 (1991).

    Article  CAS  PubMed  Google Scholar 

  3. Weil, P. A., Luse, D. S., Segall, J. & Roeder, R. G. Selective and accurate initiation of transcription at the Ad2 major late promotor in a soluble system dependent on purified RNA polymerase II and DNA. Cell 18, 469–484 (1979).

    Article  CAS  PubMed  Google Scholar 

  4. Orphanides, G., Lagrange, T. & Reinberg, D. The general transcription factors of RNA polymerase II. Genes Dev. 10, 2657–2683 (1996).

    Article  CAS  PubMed  Google Scholar 

  5. Koch, F. et al. Transcription initiation platforms and GTF recruitment at tissue-specific enhancers and promoters. Nat. Struct. Mol. Biol. 18, 956–963 (2011).

    Article  CAS  PubMed  Google Scholar 

  6. Plaschka, C. et al. Architecture of the RNA polymerase II-Mediator core initiation complex. Nature 518, 376–380 (2015).

    Article  CAS  PubMed  Google Scholar 

  7. Schier, A. C. & Taatjes, D. J. Structure and mechanism of the RNA polymerase II transcription machinery. Genes Dev. 34, 465–488 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Flanagan, P. M., Kelleher, R. J. III, Sayre, M. H., Tschochner, H. & Kornberg, R. D. A mediator required for activation of RNA polymerase II transcription in vitro. Nature 350, 436–438 (1991).

    Article  CAS  PubMed  Google Scholar 

  9. Richter, W. F., Nayak, S., Iwasa, J. & Taatjes, D. J. The Mediator complex as a master regulator of transcription by RNA polymerase II. Nat. Rev. Mol. Cell Biol. https://doi.org/10.1038/s41580-022-00498-3 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  10. Rahl, P. B. et al. c-Myc regulates transcriptional pause release. Cell 141, 432–445 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Core, L. J., Waterfall, J. J. & Lis, J. T. Nascent RNA sequencing reveals widespread pausing and divergent initiation at human promoters. Science 322, 1845–1848 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Zeitlinger, J. et al. RNA polymerase stalling at developmental control genes in the Drosophila melanogaster embryo. Nat. Genet. 39, 1512–1516 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Muse, G. W. et al. RNA polymerase is poised for activation across the genome. Nat. Genet. 39, 1507–1511 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Fant, C. B. et al. TFIID enables RNA polymerase II promoter-proximal pausing. Mol. Cell 78, 785–793 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Kwak, H. & Lis, J. T. Control of transcriptional elongation. Annu. Rev. Genet. 47, 483–508 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Li, J. et al. Kinetic competition between elongation rate and binding of NELF controls promoter-proximal pausing. Mol. Cell 50, 711–722 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Vos, S. M., Farnung, L., Urlaub, H. & Cramer, P. Structure of paused transcription complex Pol II-DSIF-NELF. Nature 560, 601–606 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Vos, S. M. et al. Structure of activated transcription complex Pol II-DSIF-PAF-SPT6. Nature 560, 607–612 (2018).

    Article  CAS  PubMed  Google Scholar 

  19. Bieniasz, P. D., Grdina, T. A., Bogerd, H. P. & Cullen, B. R. Recruitment of cyclin T1/P-TEFb to an HIV type 1 long terminal repeat promoter proximal RNA target is both necessary and sufficient for full activation of transcription. Proc. Natl Acad. Sci. USA 96, 7791–7796 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Lis, J. T., Mason, P., Peng, J., Price, D. H. & Werner, J. P-TEFb kinase recruitment and function at heat shock loci. Genes Dev. 14, 792–803 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Baillat, D. et al. Integrator, a multiprotein mediator of small nuclear RNA processing, associates with the C-terminal repeat of RNA polymerase II. Cell 123, 265–276 (2005).

    Article  CAS  PubMed  Google Scholar 

  22. Dominski, Z., Yang, X. C., Purdy, M., Wagner, E. J. & Marzluff, W. F. A CPSF-73 homologue is required for cell cycle progression but not cell growth and interacts with a protein having features of CPSF-100. Mol. Cell Biol. 25, 1489–1500 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Ezzeddine, N. et al. A subset of Drosophila integrator proteins is essential for efficient U7 snRNA and spliceosomal snRNA 3′-end formation. Mol. Cell Biol. 31, 328–341 (2011).

    Article  CAS  PubMed  Google Scholar 

  24. Wu, C. W. et al. RNA processing errors triggered by cadmium and integrator complex disruption are signals for environmental stress. BMC Biol. 17, 56 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Schmidt, D. et al. The Integrator complex regulates differential snRNA processing and fate of adult stem cells in the highly regenerative planarian Schmidtea mediterranea. PLoS Genet. 14, e1007828 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  26. Liu, Y. et al. snRNA 3′ end processing by a CPSF73-containing complex essential for development in Arabidopsis. PLoS Biol. 14, e1002571 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  27. Chen, J. et al. An RNAi screen identifies additional members of the Drosophila integrator complex and a requirement for cyclin C/Cdk8 in snRNA 3′-end formation. RNA 18, 2148–2156 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Pfleiderer, M. M. & Galej, W. P. Structure of the catalytic core of the Integrator complex. Mol. Cell 81, 1246–1259 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Sabath, K. et al. INTS10-INTS13-INTS14 form a functional module of Integrator that binds nucleic acids and the cleavage module. Nat. Commun. 11, 3422 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Barbieri, E. et al. Targeted enhancer activation by a subunit of the integrator complex. Mol. Cell 71, 103–116 (2018). Partition of Integrator into distinct functional modules is first proposed, with the identification of the enhancer module.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Vervoort, S. J. et al. The PP2A-Integrator-CDK9 axis fine-tunes transcription and can be targeted therapeutically in cancer. Cell 184, 3143–3162 (2021). The Int–PP2A module of Integrator is identified as functionally opposing CDK9 activity at most protein-coding genes.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Fianu, I. et al. Structural basis of Integrator-mediated transcription regulation. Science 374, 883–887 (2021). This study presents Integrator’s structure in association with reconstituted pausing Pol II, with an active INTS11 catalytic site.

    Article  CAS  PubMed  Google Scholar 

  33. Zheng, H. et al. Identification of Integrator-PP2A complex (INTAC), an RNA polymerase II phosphatase. Science 370, eabb5872 (2020). The first cryogenic electron microscopy analysis of Integrator reveals how core components assemble and identify the phosphatase module.

    Article  CAS  PubMed  Google Scholar 

  34. Huang, K. L. et al. Integrator recruits protein phosphatase 2A to prevent pause release and facilitate transcription termination. Mol. Cell 80, 345–358 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Rengachari, S., Schilbach, S., Aibara, S., Dienemann, C. & Cramer, P. Structure of the human mediator-RNA polymerase II pre-initiation complex. Nature 594, 129–133 (2021).

    Article  CAS  PubMed  Google Scholar 

  36. Abdella, R. et al. Structure of the human mediator-bound transcription preinitiation complex. Science 372, 52–56 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Sun, Y. et al. Structure of an active human histone pre-mRNA 3′-end processing machinery. Science 367, 700–703 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Wu, Y., Albrecht, T. R., Baillat, D., Wagner, E. J. & Tong, L. Molecular basis for the interaction between Integrator subunits IntS9 and IntS11 and its functional importance. Proc. Natl Acad. Sci. USA 114, 4394–4399 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Albrecht, T. R. et al. Integrator subunit 4 is a ‘Symplekin-like’ scaffold that associates with INTS9/11 to form the Integrator cleavage module. Nucleic Acids Res. 46, 4241–4255 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Lambrecht, C., Haesen, D., Sents, W., Ivanova, E. & Janssens, V. Structure, regulation, and pharmacological modulation of PP2A phosphatases. Methods Mol. Biol. 1053, 283–305 (2013).

    Article  CAS  PubMed  Google Scholar 

  41. Xu, Y. et al. Structure of the protein phosphatase 2A holoenzyme. Cell 127, 1239–1251 (2006).

    Article  CAS  PubMed  Google Scholar 

  42. Cho, U. S. & Xu, W. Crystal structure of a protein phosphatase 2A heterotrimeric holoenzyme. Nature 445, 53–57 (2007).

    Article  CAS  PubMed  Google Scholar 

  43. Seshacharyulu, P., Pandey, P., Datta, K. & Batra, S. K. Phosphatase: PP2A structural importance, regulation and its aberrant expression in cancer. Cancer Lett. 335, 9–18 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Ren, W. et al. Structural basis of SOSS1 complex assembly and recognition of ssDNA. Cell Rep. 6, 982–991 (2014).

    Article  CAS  PubMed  Google Scholar 

  45. Arcus, V. OB-fold domains: a snapshot of the evolution of sequence, structure and function. Curr. Opin. Struct. Biol. 12, 794–801 (2002).

    Article  CAS  PubMed  Google Scholar 

  46. Zhang, F., Ma, T. & Yu, X. A core hSSB1-INTS complex participates in the DNA damage response. J. Cell Sci. 126, 4850–4855 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Jia, Y. et al. Crystal structure of the INTS3/INTS6 complex reveals the functional importance of INTS3 dimerization in DSB repair. Cell Discov. 7, 66 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Li, J. et al. Structural basis for multifunctional roles of human Ints3 C-terminal domain. J. Biol. Chem. 296, 100112 (2021).

    Article  CAS  PubMed  Google Scholar 

  49. Nojima, T. & Proudfoot, N. J. Mechanisms of lncRNA biogenesis as revealed by nascent transcriptomics. Nat. Rev. Mol. Cell Biol. https://doi.org/10.1038/s41580-021-00447-6 (2022).

    Article  PubMed  Google Scholar 

  50. Hernandez, N. Small nuclear RNA genes: a model system to study fundamental mechanisms of transcription. J. Biol. Chem. 276, 26733–26736 (2001).

    Article  CAS  PubMed  Google Scholar 

  51. Wilkinson, M. E., Charenton, C. & Nagai, K. RNA splicing by the spliceosome. Annu. Rev. Biochem. 89, 359–388 (2020).

    Article  CAS  PubMed  Google Scholar 

  52. Guiro, J. & Murphy, S. Regulation of expression of human RNA polymerase II-transcribed snRNA genes. Open Biol. https://doi.org/10.1098/rsob.170073 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  53. Mandel, C. R. et al. Polyadenylation factor CPSF-73 is the pre-mRNA 3′-end-processing endonuclease. Nature 444, 953–956 (2006).

    Article  CAS  PubMed  Google Scholar 

  54. Egloff, S., O’Reilly, D. & Murphy, S. Expression of human snRNA genes from beginning to end. Biochem. Soc. Trans. 36, 590–594 (2008).

    Article  CAS  PubMed  Google Scholar 

  55. Hernandez, N. & Weiner, A. M. Formation of the 3′ end of U1 snRNA requires compatible snRNA promoter elements. Cell 47, 249–258 (1986).

    Article  CAS  PubMed  Google Scholar 

  56. de Vegvar, H. E., Lund, E. & Dahlberg, J. E. 3′ end formation of U1 snRNA precursors is coupled to transcription from snRNA promoters. Cell 47, 259–266 (1986).

    Article  PubMed  Google Scholar 

  57. Hernandez, N. Formation of the 3′ end of U1 snRNA is directed by a conserved sequence located downstream of the coding region. EMBO J. 4, 1827–1837 (1985).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Lai, F., Gardini, A., Zhang, A. & Shiekhattar, R. Integrator mediates the biogenesis of enhancer RNAs. Nature 525, 399–403 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Gomez-Orte, E. et al. Disruption of the Caenorhabditis elegans Integrator complex triggers a non-conventional transcriptional mechanism beyond snRNA genes. PLoS Genet. 15, e1007981 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Davidson, L., Francis, L., Eaton, J. D. & West, S. Integrator-dependent and allosteric/intrinsic mechanisms ensure efficient termination of snRNA transcription. Cell Rep. 33, 108319 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Egloff, S. et al. The integrator complex recognizes a new double mark on the RNA polymerase II carboxyl-terminal domain. J. Biol. Chem. 285, 20564–20569 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Ebmeier, C. C. et al. Human TFIIH kinase CDK7 regulates transcription-associated chromatin modifications. Cell Rep. 20, 1173–1186 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Yamamoto, J. et al. DSIF and NELF interact with Integrator to specify the correct post-transcriptional fate of snRNA genes. Nat. Commun. 5, 4263 (2014).

    Article  CAS  PubMed  Google Scholar 

  64. Tatomer, D. C. et al. The Integrator complex cleaves nascent mRNAs to attenuate transcription. Genes Dev. 33, 1525–1538 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. O’Reilly, D. et al. Human snRNA genes use polyadenylation factors to promote efficient transcription termination. Nucleic Acids Res. 42, 264–275 (2014).

    Article  PubMed  Google Scholar 

  66. Baillat, D., Gardini, A., Cesaroni, M. & Shiekhattar, R. Requirement for SNAPC1 in transcriptional responsiveness to diverse extracellular signals. Mol. Cell Biol. 32, 4642–4650 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Waldschmidt, R., Wanandi, I. & Seifart, K. H. Identification of transcription factors required for the expression of mammalian U6 genes in vitro. EMBO J. 10, 2595–2603 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Raha, D. et al. Close association of RNA polymerase II and many transcription factors with Pol III genes. Proc. Natl Acad. Sci. USA 107, 3639–3644 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. 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 

  70. Adam, R. C. et al. Pioneer factors govern super-enhancer dynamics in stem cell plasticity and lineage choice. Nature 521, 366–370 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. 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 

  72. Arner, E. et al. Transcribed enhancers lead waves of coordinated transcription in transitioning mammalian cells. Science 347, 1010–1014 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Field, A. & Adelman, K. Evaluating enhancer function and transcription. Annu. Rev. Biochem. 89, 213–234 (2020).

    Article  CAS  PubMed  Google Scholar 

  74. Schoenfelder, S. & Fraser, P. Long-range enhancer-promoter contacts in gene expression control. Nat. Rev. Genet. 20, 437–455 (2019).

    Article  CAS  PubMed  Google Scholar 

  75. Andersson, R. et al. An atlas of active enhancers across human cell types and tissues. Nature 507, 455–461 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Kim, T. K. et al. Widespread transcription at neuronal activity-regulated enhancers. Nature 465, 182–187 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Statello, L., Guo, C. J., Chen, L. L. & Huarte, M. Gene regulation by long non-coding RNAs and its biological functions. Nat. Rev. Mol. Cell Biol. 22, 96–118 (2021).

    Article  CAS  PubMed  Google Scholar 

  78. De Santa, F. et al. A large fraction of extragenic RNA pol II transcription sites overlap enhancers. PLoS Biol. 8, e1000384 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  79. Gil, N. & Ulitsky, I. Production of spliced long noncoding RNAs specifies regions with increased enhancer activity. Cell Syst. 7, 537–547 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. van den Berg, D. L. C. et al. Nipbl Interacts with Zfp609 and the Integrator complex to regulate cortical neuron migration. Neuron 93, 348–361 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  81. Gurumurthy, A. et al. Super-enhancer mediated regulation of adult beta-globin gene expression: the role of eRNA and Integrator. Nucleic Acids Res. 49, 1383–1396 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Nojima, T. et al. Deregulated expression of mammalian lncRNA through loss of SPT6 induces R-loop formation, replication stress, and cellular senescence. Mol. Cell 72, 970–984 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Cazalla, D., Xie, M. & Steitz, J. A. A primate herpesvirus uses the integrator complex to generate viral microRNAs. Mol. Cell 43, 982–992 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Xie, M. et al. The host Integrator complex acts in transcription-independent maturation of herpesvirus microRNA 3′ ends. Genes Dev. 29, 1552–1564 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Kirstein, N. et al. The Integrator complex regulates microRNA abundance through RISC loading. Preprint at bioRxiv https://doi.org/10.1101/2021.09.21.461113 (2021).

    Article  Google Scholar 

  86. Ozata, D. M., Gainetdinov, I., Zoch, A., O’Carroll, D. & Zamore, P. D. PIWI-interacting RNAs: small RNAs with big functions. Nat. Rev. Genet. 20, 89–108 (2019).

    Article  CAS  PubMed  Google Scholar 

  87. Beltran, T., Pahita, E., Ghosh, S., Lenhard, B. & Sarkies, P. Integrator is recruited to promoter-proximally paused RNA Pol II to generate Caenorhabditis elegans piRNA precursors. EMBO J. 40, e105564 (2021).

    Article  CAS  PubMed  Google Scholar 

  88. Berkyurek, A. C. et al. The RNA polymerase II subunit RPB-9 recruits the integrator complex to terminate Caenorhabditis elegans piRNA transcription. EMBO J. 40, e105565 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Czech, B., Preall, J. B., McGinn, J. & Hannon, G. J. A transcriptome-wide RNAi screen in the Drosophila ovary reveals factors of the germline piRNA pathway. Mol. Cell 50, 749–761 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Handler, D. et al. The genetic makeup of the Drosophila piRNA pathway. Mol. Cell 50, 762–777 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Shay, J. W. & Wright, W. E. Telomeres and telomerase: three decades of progress. Nat. Rev. Genet. 20, 299–309 (2019).

    Article  CAS  PubMed  Google Scholar 

  92. Rubtsova, M. P. et al. Integrator is a key component of human telomerase RNA biogenesis. Sci. Rep. 9, 1701 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Clemson, C. M. et al. An architectural role for a nuclear noncoding RNA: NEAT1 RNA is essential for the structure of paraspeckles. Mol. Cell 33, 717–726 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Barra, J. et al. Integrator restrains paraspeckles assembly by promoting isoform switching of the lncRNA NEAT1. Sci. Adv. 6, eaaz9072 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Naganuma, T. et al. Alternative 3′-end processing of long noncoding RNA initiates construction of nuclear paraspeckles. EMBO J. 31, 4020–4034 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Rasmussen, E. B. & Lis, J. T. In vivo transcriptional pausing and cap formation on three Drosophila heat shock genes. Proc. Natl Acad. Sci. USA 90, 7923–7927 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Core, L. J. & Lis, J. T. Transcription regulation through promoter-proximal pausing of RNA polymerase II. Science 319, 1791–1792 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Adelman, K. & Lis, J. T. Promoter-proximal pausing of RNA polymerase II: emerging roles in metazoans. Nat. Rev. Genet. 13, 720–731 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Chen, F. X. et al. PAF1, a molecular regulator of promoter-proximal pausing by RNA polymerase II. Cell 162, 1003–1015 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Chen, F. X. et al. PAF1 regulation of promoter-proximal pause release via enhancer activation. Science 357, 1294–1298 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Core, L. J. et al. Defining the status of RNA polymerase at promoters. Cell Rep. 2, 1025–1035 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Liu, J., Wu, X., Zhang, H., Pfeifer, G. P. & Lu, Q. Dynamics of RNA polymerase II pausing and bivalent histone H3 methylation during neuronal differentiation in brain development. Cell Rep. 20, 1307–1318 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Gaertner, B. & Zeitlinger, J. RNA polymerase II pausing during development. Development 141, 1179–1183 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Danko, C. G. et al. Signaling pathways differentially affect RNA polymerase II initiation, pausing, and elongation rate in cells. Mol. Cell 50, 212–222 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Galbraith, M. D. et al. HIF1A employs CDK8-mediator to stimulate RNAPII elongation in response to hypoxia. Cell 153, 1327–1339 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Nilson, K. A. et al. Oxidative stress rapidly stabilizes promoter-proximal paused Pol II across the human genome. Nucleic Acids Res. 45, 11088–11105 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Andrulis, E. D., Guzman, E., Doring, P., Werner, J. & Lis, J. T. High-resolution localization of Drosophila Spt5 and Spt6 at heat shock genes in vivo: roles in promoter proximal pausing and transcription elongation. Genes Dev. 14, 2635–2649 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Gardini, A. et al. Integrator regulates transcriptional initiation and pause release following activation. Mol. Cell 56, 128–139 (2014). The first genome-wide analysis of Integrator occupancy reveals diffuse binding at Pol II genes and a requirement for stimulus-dependent transcriptional activation.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Beckedorff, F. et al. The human Integrator complex facilitates transcriptional elongation by endonucleolytic cleavage of nascent transcripts. Cell Rep. 32, 107917 (2020). This study proposes an RNA cleavage-dependent mechanism that promotes productive Pol II elongation in mammals.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Stadelmayer, B. et al. Integrator complex regulates NELF-mediated RNA polymerase II pause/release and processivity at coding genes. Nat. Commun. 5, 5531 (2014).

    Article  CAS  PubMed  Google Scholar 

  111. Elrod, N. D. et al. The integrator complex attenuates promoter-proximal transcription at protein-coding genes. Mol. Cell 76, 738–752 (2019). This study implicates the Integrator complex in transcription attenuation of protein-coding genes, via the endonuclease module.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Aoi, Y. et al. NELF regulates a promoter-proximal step distinct from RNA Pol II pause-release. Mol. Cell 78, 261–274 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Shersher, E. et al. NACK and INTEGRATOR act coordinately to activate Notch-mediated transcription in tumorigenesis. Cell Commun. Signal. 19, 96 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Kamieniarz-Gdula, K. et al. Selective roles of vertebrate PCF11 in premature and full-length transcript termination. Mol. Cell 74, 158–172 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Kamieniarz-Gdula, K. & Proudfoot, N. J. Transcriptional control by premature termination: a forgotten mechanism. Trends Genet. 35, 553–564 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Lykke-Andersen, S. et al. Integrator is a genome-wide attenuator of non-productive transcription. Mol. Cell 81, 514–529 (2021).

    Article  CAS  PubMed  Google Scholar 

  117. Skaar, J. R. et al. The Integrator complex controls the termination of transcription at diverse classes of gene targets. Cell Res. 25, 288–305 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Dasilva, L. F. et al. Integrator enforces the fidelity of transcriptional termination at protein-coding genes. Sci. Adv. 7, eabe3393 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Rosa-Mercado, N. A. et al. Hyperosmotic stress alters the RNA polymerase II interactome and induces readthrough transcription despite widespread transcriptional repression. Mol. Cell 81, 502–513 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Cossa, G., Parua, P. K., Eilers, M. & Fisher, R. P. Protein phosphatases in the RNAPII transcription cycle: erasers, sculptors, gatekeepers, and potential drug targets. Genes Dev. 35, 658–676 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Sents, W., Ivanova, E., Lambrecht, C., Haesen, D. & Janssens, V. The biogenesis of active protein phosphatase 2A holoenzymes: a tightly regulated process creating phosphatase specificity. FEBS J. 280, 644–661 (2013).

    Article  CAS  PubMed  Google Scholar 

  122. Malovannaya, A. et al. Analysis of the human endogenous coregulator complexome. Cell 145, 787–799 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Malovannaya, A. et al. Streamlined analysis schema for high-throughput identification of endogenous protein complexes. Proc. Natl Acad. Sci. USA 107, 2431–2436 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Core, L. & Adelman, K. Promoter-proximal pausing of RNA polymerase II: a nexus of gene regulation. Genes Dev. 33, 960–982 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Jeronimo, C., Collin, P. & Robert, F. The RNA polymerase II CTD: the increasing complexity of a low-complexity protein domain. J. Mol. Biol. 428, 2607–2622 (2016).

    Article  CAS  PubMed  Google Scholar 

  126. Galbraith, M. D., Bender, H. & Espinosa, J. M. Therapeutic targeting of transcriptional cyclin-dependent kinases. Transcription 10, 118–136 (2019).

    Article  CAS  PubMed  Google Scholar 

  127. Parua, P. K. & Fisher, R. P. Dissecting the Pol II transcription cycle and derailing cancer with CDK inhibitors. Nat. Chem. Biol. 16, 716–724 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Luo, Z., Lin, C. & Shilatifard, A. The super elongation complex (SEC) family in transcriptional control. Nat. Rev. Mol. Cell Biol. 13, 543–547 (2012).

    Article  CAS  PubMed  Google Scholar 

  129. Hu, S. et al. SPT5 stabilizes RNA polymerase II, orchestrates transcription cycles, and maintains the enhancer landscape. Mol. Cell 81, 4425–4439 (2021).

    Article  CAS  PubMed  Google Scholar 

  130. Parua, P. K., Kalan, S., Benjamin, B., Sanso, M. & Fisher, R. P. Distinct Cdk9-phosphatase switches act at the beginning and end of elongation by RNA polymerase II. Nat. Commun. 11, 4338 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Parua, P. K. et al. A Cdk9-PP1 switch regulates the elongation-termination transition of RNA polymerase II. Nature 558, 460–464 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Mascibroda, L. G. et al. INTS13 mutations causing a developmental ciliopathy disrupt Integrator complex assembly. Preprint at bioRxiv https://doi.org/10.1101/2020.07.20.209130 (2020).

    Article  Google Scholar 

  133. Skaar, J. R. et al. INTS3 controls the hSSB1-mediated DNA damage response. J. Cell Biol. 187, 25–32 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Li, Y. et al. HSSB1 and hSSB2 form similar multiprotein complexes that participate in DNA damage response. J. Biol. Chem. 284, 23525–23531 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Huang, J., Gong, Z., Ghosal, G. & Chen, J. SOSS complexes participate in the maintenance of genomic stability. Mol. Cell 35, 384–393 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Byrne, B. M. & Oakley, G. G. Replication protein A, the laxative that keeps DNA regular: the importance of RPA phosphorylation in maintaining genome stability. Semin. Cell Dev. Biol. 86, 112–120 (2019).

    Article  CAS  PubMed  Google Scholar 

  137. Richard, D. J. et al. Single-stranded DNA-binding protein hSSB1 is critical for genomic stability. Nature 453, 677–681 (2008).

    Article  CAS  PubMed  Google Scholar 

  138. Richard, D. J. et al. hSSB1 rapidly binds at the sites of DNA double-strand breaks and is required for the efficient recruitment of the MRN complex. Nucleic Acids Res. 39, 1692–1702 (2011).

    Article  CAS  PubMed  Google Scholar 

  139. Richard, D. J. et al. hSSB1 interacts directly with the MRN complex stimulating its recruitment to DNA double-strand breaks and its endo-nuclease activity. Nucleic Acids Res. 39, 3643–3651 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Oegema, R. et al. Human mutations in integrator complex subunits link transcriptome integrity to brain development. PLoS Genet. 13, e1006809 (2017). This is the first report indicating that recessive mutations of Integrator subunits are linked to severe developmental disorders.

    Article  PubMed  PubMed Central  Google Scholar 

  141. Yoshimi, A. et al. Coordinated alterations in RNA splicing and epigenetic regulation drive leukaemogenesis. Nature 574, 273–277 (2019). This study demonstrates that loss of a subunit of Integrator, INTS3, functions as a driver of leukaemogenesis.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Kheirallah, A. K., de Moor, C. H., Faiz, A., Sayers, I. & Hall, I. P. Lung function associated gene Integrator complex subunit 12 regulates protein synthesis pathways. BMC Genomics 18, 248 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  143. Hata, T. & Nakayama, M. Targeted disruption of the murine large nuclear KIAA1440/Ints1 protein causes growth arrest in early blastocyst stage embryos and eventual apoptotic cell death. Biochim. Biophys. Acta 1773, 1039–1051 (2007).

    Article  CAS  PubMed  Google Scholar 

  144. Kapp, L. D., Abrams, E. W., Marlow, F. L. & Mullins, M. C. The integrator complex subunit 6 (Ints6) confines the dorsal organizer in vertebrate embryogenesis. PLoS Genet. 9, e1003822 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  145. Huang, H. et al. The integrator complex subunit 11 is involved in the post-diapaused embryonic development and stress response of Artemia sinica. Gene 741, 144548 (2020).

    Article  CAS  PubMed  Google Scholar 

  146. Tao, S., Cai, Y. & Sampath, K. The Integrator subunits function in hematopoiesis by modulating Smad/BMP signaling. Development 136, 2757–2765 (2009).

    Article  CAS  PubMed  Google Scholar 

  147. Zhang, P. et al. INTS11 regulates hematopoiesis by promoting PRC2 function. Sci. Adv. 7, eabh1684 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Otani, Y. et al. Integrator complex plays an essential role in adipose differentiation. Biochem. Biophys. Res. Commun. 434, 197–202 (2013).

    Article  CAS  PubMed  Google Scholar 

  149. Zhang, Y. et al. The Integrator complex prevents dedifferentiation of intermediate neural progenitors back into neural stem cells. Cell Rep. 27, 987–996 (2019).

    Article  CAS  PubMed  Google Scholar 

  150. Krall, M. et al. Biallelic sequence variants in INTS1 in patients with developmental delays, cataracts, and craniofacial anomalies. Eur. J. Hum. Genet. 27, 582–593 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  151. Zhang, X. et al. Biallelic INTS1 mutations cause a rare neurodevelopmental disorder in two Chinese siblings. J. Mol. Neurosci. 70, 1–8 (2020).

    Article  PubMed  Google Scholar 

  152. Bacon, C. & Rappold, G. A. The distinct and overlapping phenotypic spectra of FOXP1 and FOXP2 in cognitive disorders. Hum. Genet. 131, 1687–1698 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Lenaerts, L. et al. The broad phenotypic spectrum of PPP2R1A-related neurodevelopmental disorders correlates with the degree of biochemical dysfunction. Genet. Med. 23, 352–362 (2021).

    Article  CAS  PubMed  Google Scholar 

  154. Zhang, Y. et al. A de novo variant identified in the PPP2R1A gene in an infant induces neurodevelopmental abnormalities. Neurosci. Bull. 36, 179–182 (2020).

    Article  PubMed  Google Scholar 

  155. Wallace, A., Caruso, P. & Karaa, A. A newborn with severe ventriculomegaly: expanding the PPP2R1A gene mutation phenotype. J. Pediatr. Genet. 8, 240–243 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Houge, G. et al. B56delta-related protein phosphatase 2A dysfunction identified in patients with intellectual disability. J. Clin. Invest. 125, 3051–3062 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  157. Deciphering Developmental Disorders Study. Large-scale discovery of novel genetic causes of developmental disorders. Nature 519, 223–228 (2015).

    Article  Google Scholar 

  158. Tilley, F. C. et al. Disruption of pathways regulated by Integrator complex in Galloway-Mowat syndrome due to WDR73 mutations. Sci. Rep. 11, 5388 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Wheway, G., Nazlamova, L. & Hancock, J. T. Signaling through the primary cilium. Front. Cell Dev. Biol. 6, 8 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  160. Jodoin, J. N. et al. Nuclear-localized Asunder regulates cytoplasmic dynein localization via its role in the integrator complex. Mol. Biol. Cell 24, 2954–2965 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Jodoin, J. N. et al. The snRNA-processing complex, Integrator, is required for ciliogenesis and dynein recruitment to the nuclear envelope via distinct mechanisms. Biol. Open 2, 1390–1396 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  162. Mittal, P. & Roberts, C. W. M. The SWI/SNF complex in cancer - biology, biomarkers and therapy. Nat. Rev. Clin. Oncol. 17, 435–448 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Federico, A. et al. Pan-cancer mutational and transcriptional analysis of the integrator complex. Int. J. Mol. Sci. https://doi.org/10.3390/ijms18050936 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  164. Van den Eynden, J., Basu, S. & Larsson, E. Somatic mutation patterns in hemizygous genomic regions unveil purifying selection during tumor evolution. PLoS Genet. 12, e1006506 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  165. Yue, J. et al. Integrator orchestrates RAS/ERK1/2 signaling transcriptional programs. Genes Dev. 31, 1809–1820 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Tong, H. et al. INTS8 accelerates the epithelial-to-mesenchymal transition in hepatocellular carcinoma by upregulating the TGF-beta signaling pathway. Cancer Manag. Res. 11, 1869–1879 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Inagaki, Y. et al. CREB3L4, INTS3, and SNAPAP are targets for the 1q21 amplicon frequently detected in hepatocellular carcinoma. Cancer Genet. Cytogenet. 180, 30–36 (2008).

    Article  CAS  PubMed  Google Scholar 

  168. Wieland, I. et al. Isolation of DICE1: a gene frequently affected by LOH and downregulated in lung carcinomas. Oncogene 18, 4530–4537 (1999).

    Article  CAS  PubMed  Google Scholar 

  169. Filleur, S. et al. INTS6/DICE1 inhibits growth of human androgen-independent prostate cancer cells by altering the cell cycle profile and Wnt signaling. Cancer Cell Int. 9, 28 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  170. Li, J. et al. Bioinformatics analysis of gene expression profiles in childhood B-precursor acute lymphoblastic leukemia. Hematology 20, 377–383 (2015).

    Article  CAS  PubMed  Google Scholar 

  171. Ropke, A. et al. Promoter CpG hypermethylation and downregulation of DICE1 expression in prostate cancer. Oncogene 24, 6667–6675 (2005).

    Article  PubMed  Google Scholar 

  172. Perrotti, D. & Neviani, P. Protein phosphatase 2A: a target for anticancer therapy. Lancet Oncol. 14, e229–e238 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. O’Connor, C. M. et al. Inactivation of PP2A by a recurrent mutation drives resistance to MEK inhibitors. Oncogene 39, 703–717 (2020).

    Article  PubMed  Google Scholar 

  174. Taylor, S. E. et al. The highly recurrent PP2A Aalpha-subunit mutation P179R alters protein structure and impairs PP2A enzyme function to promote endometrial tumorigenesis. Cancer Res. 79, 4242–4257 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. Cherniack, A. D. et al. Integrated molecular characterization of uterine carcinosarcoma. Cancer Cell 31, 411–423 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  176. Haesen, D. et al. Recurrent PPP2R1A mutations in uterine cancer act through a dominant-negative mechanism to promote malignant cell growth. Cancer Res. 76, 5719–5731 (2016).

    Article  CAS  PubMed  Google Scholar 

  177. Shih Ie, M. et al. Somatic mutations of PPP2R1A in ovarian and uterine carcinomas. Am. J. Pathol. 178, 1442–1447 (2011).

    Article  PubMed  Google Scholar 

  178. Bockelman, C. et al. Prognostic role of CIP2A expression in serous ovarian cancer. Br. J. Cancer 105, 989–995 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  179. Leonard, D. et al. Selective PP2A enhancement through biased heterotrimer stabilization. Cell 181, 688–701 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  180. Neviani, P. et al. PP2A-activating drugs selectively eradicate TKI-resistant chronic myeloid leukemic stem cells. J. Clin. Invest. 123, 4144–4157 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  181. Kastrinsky, D. B. et al. Reengineered tricyclic anti-cancer agents. Bioorg. Med. Chem. 23, 6528–6534 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  182. Harlen, K. M. & Churchman, L. S. The code and beyond: transcription regulation by the RNA polymerase II carboxy-terminal domain. Nat. Rev. Mol. Cell Biol. 18, 263–273 (2017).

    Article  CAS  PubMed  Google Scholar 

  183. Schuller, R. et al. Heptad-specific phosphorylation of RNA polymerase II CTD. Mol. Cell 61, 305–314 (2016).

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

Work in the Gardini laboratory is supported by grants from the NIH (R01 HL141326 and CA252223), the American Cancer Society (RSG-18-157-01-DMC) and the G. Harold and Leila Y. Mathers Charitable Foundation (A.G.).

Author information

Authors and Affiliations

Authors

Contributions

Both authors researched data for the article and substantially contributed to discussion of the content. A.G. wrote the article and reviewed and/or edited the manuscript before submission.

Corresponding author

Correspondence to Alessandro Gardini.

Ethics declarations

Competing interests

The authors declare no competing interests.

Peer review

Peer review information

Nature Reviews Molecular Cell Biology thanks Nick Proudfoot and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Additional information

Publisher’s note

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

Related links

The Cancer Genome Atlas: https://www.cancer.gov/about-nci/organization/ccg/research/structural-genomics/tcga

Glossary

Carboxy-terminal domain

(CTD). The unstructured and highly repetitive C terminus of the largest subunit of RNA polymerase II. The CTD has roles in transcription regulation and co-transcriptional RNA processing.

Metallo-β-lactamase–β-CASP domain

(MBL–β-CASP). A metallo-β-lactamase fold further extending into a β-CASP globular domain to form an active nuclease site.

U small nuclear RNAs

(U snRNAs). Uridine-rich small nuclear RNAs transcribed by RNA polymerase II that have essential roles in pre-mRNA splicing.

von Willebrand factor type A domain

An alternating sequence of α-helices and β-strands, generally mediating protein–protein interactions.

HEAT repeats

Protein structural motifs composed of tandem repeats of two α-helices linked by a short loop.

OB-fold domain

The oligonucleotide- or oligosaccharide-binding fold is an evolutionarily ancient protein domain capable of binding nucleic acids.

Premature transcription termination

A process that generally occurs when elongating RNA polymerase II is arrested at any point after the transcription start site and before it reaches a canonical termination site, usually resulting in release of unstable transcripts.

Rights and permissions

Springer Nature or its licensor holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Welsh, S.A., Gardini, A. Genomic regulation of transcription and RNA processing by the multitasking Integrator complex. Nat Rev Mol Cell Biol (2022). https://doi.org/10.1038/s41580-022-00534-2

Download citation

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1038/s41580-022-00534-2

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