Review Article | Published:

Mechanisms of action and regulation of ATP-dependent chromatin-remodelling complexes

Nature Reviews Molecular Cell Biology volume 18, pages 407422 (2017) | Download Citation

Abstract

Cells utilize diverse ATP-dependent nucleosome-remodelling complexes to carry out histone sliding, ejection or the incorporation of histone variants, suggesting that different mechanisms of action are used by the various chromatin-remodelling complex subfamilies. However, all chromatin-remodelling complex subfamilies contain an ATPase–translocase 'motor' that translocates DNA from a common location within the nucleosome. In this Review, we discuss (and illustrate with animations) an alternative, unifying mechanism of chromatin remodelling, which is based on the regulation of DNA translocation. We propose the 'hourglass' model of remodeller function, in which each remodeller subfamily utilizes diverse specialized proteins and protein domains to assist in nucleosome targeting or to differentially detect nucleosome epitopes. These modules converge to regulate a common DNA translocation mechanism, to inform the conserved ATPase 'motor' on whether and how to apply DNA translocation, which together achieve the various outcomes of chromatin remodelling: nucleosome assembly, chromatin access and nucleosome editing.

Key points

  • The dynamic regulation of chromatin involves four subfamilies of ATP-dependent nucleosome-remodelling complexes: imitation switch (ISWI), chromodomain helicase DNA-binding (CHD), switch/sucrose non-fermentable (SWI/SNF) and INO80. Each subfamily is specialized to preferentially achieve particular chromatin outcomes: assembly, access or editing.

  • Diversity in the protein composition of remodellers enables their specific interaction with particular transcription activators, repressors and histone modifications, which together specify targeting.

  • Although diverse in protein composition, all remodellers have a similar ATPase 'motor' that translocates DNA from a common location within the nucleosome, which breaks histone–DNA contacts.

  • The diverse specialized proteins and domains in each remodeller subfamily are also involved in detecting nucleosome epitopes, which differentially regulate the conserved ATPase–translocase motor to achieve the various chromatin-remodelling outcomes.

  • We propose an 'hourglass' model of chromatin remodelling that involves convergence on a DNA translocation mechanism, which is preceded and followed by remodeller diversity, in terms of differential remodeller targeting and remodelling outcomes, respectively.

  • Remodellers are emerging as 'smart' machines that are informed about whether or how to utilize DNA translocation to conduct chromatin remodelling.

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References

  1. 1.

    & in Fundamentals of Chromatin (eds Workman, J. L. & Abmayr, S. M.) 69–146 (Springer, 2014).

  2. 2.

    & Chromatin remodelling during development. Nature 463, 474–484 (2010).

  3. 3.

    & SWI/SNF nucleosome remodellers and cancer. Nat. Rev. Cancer 11, 481–492 (2011).

  4. 4.

    & Cancer biology and NuRD: a multifaceted chromatin remodelling complex. Nat. Rev. Cancer 11, 588–596 (2011).

  5. 5.

    & The biology of chromatin remodeling complexes. Annu. Rev. Biochem. 78, 273–304 (2009).

  6. 6.

    Regulating the chromatin landscape: structural and mechanistic perspectives. Annu. Rev. Biochem. 83, 671–696 (2014).

  7. 7.

    , & Mechanisms and functions of ATP-dependent chromatin-remodeling enzymes. Cell 154, 490–503 (2013).

  8. 8.

    & ATP-dependent chromatin remodeling: genetics, genomics and mechanisms. Cell Res. 21, 396–420 (2011).

  9. 9.

    & Nucleosome remodeling and epigenetics. Cold Spring Harb. Perspect. Biol. (2013).

  10. 10.

    , , & Identification of multiple distinct Snf2 subfamilies with conserved structural motifs. Nucleic Acids Res. 34, 2887–2905 (2006).

  11. 11.

    , & Histone chaperones: assisting histone traffic and nucleosome dynamics. Annu. Rev. Biochem. 83, 487–517 (2014).

  12. 12.

    , , , & Identification of a rapidly formed nonnucleosomal histone-DNA intermediate that is converted into chromatin by ACF. Mol. Cell 43, 638–648 (2011).

  13. 13.

    et al. The prenucleosome, a stable conformational isomer of the nucleosome. Genes Dev. 29, 2563–2575 (2015).

  14. 14.

    et al. ISWI is an ATP-dependent nucleosome remodeling factor. Mol. Cell 3, 239–245 (1999).

  15. 15.

    et al. Chromatin-remodelling factor CHRAC contains the ATPases ISWI and topoisomerase II. Nature 388, 598–602 (1997); erratum 389, 1003 (1997).

  16. 16.

    , & Distinct activities of CHD1 and ACF in ATP-dependent chromatin assembly. Nat. Struct. Mol. Biol. 12, 160–166 (2005).

  17. 17.

    , , , & ACF, an ISWI-containing and ATP-utilizing chromatin assembly and remodeling factor. Cell 90, 145–155 (1997).

  18. 18.

    , , & Removal of promoter nucleosomes by disassembly rather than sliding in vivo. Mol. Cell 14, 667–673 (2004).

  19. 19.

    et al. ATP-driven exchange of histone H2AZ variant catalyzed by SWR1 chromatin remodeling complex. Science 303, 343–348 (2004). This study demonstrated for the first time that SWR1C carries out nucleosome editing that involves H2A.Z.

  20. 20.

    et al. Purification of a human SRCAP complex that remodels chromatin by incorporating the histone variant H2A. Z into nucleosomes. Biochemistry 45, 5671–5677 (2006).

  21. 21.

    et al. Distinct factors control histone variant H3.3 localization at specific genomic regions. Cell 140, 678–691 (2010).

  22. 22.

    et al. Direct observation of DNA distortion by the RSC complex. Mol. Cell 21, 417–425 (2006).

  23. 23.

    et al. DNA translocation and loop formation mechanism of chromatin remodeling by SWI/SNF and RSC. Mol. Cell 24, 559–568 (2006).

  24. 24.

    et al. The RSC chromatin remodelling ATPase translocates DNA with high force and small step size. EMBO J. 30, 2364–2372 (2011).

  25. 25.

    et al. Stepwise nucleosome translocation by RSC remodeling complexes. eLife 5, e10051 (2016).

  26. 26.

    , , , & Dynamics of nucleosome remodelling by individual ACF complexes. Nature 462, 1022–1027 (2009). References 23–26 investigate the size of the DNA step that occurs during DNA translocation by SWI/SNF remodellers.

  27. 27.

    & ISWI induces nucleosome sliding on nicked DNA. Mol. Cell 8, 1085–1092 (2001).

  28. 28.

    , & Chromatin remodeling by RSC involves ATP-dependent DNA translocation. Genes Dev. 16, 2120–2134 (2002).

  29. 29.

    , , , & Evidence for DNA translocation by the ISWI chromatin-remodeling enzyme. Mol. Cell. Biol. 23, 1935–1945 (2003). References 28 and 29 demonstrated for the first time that chromatin remodellers act by DNA translocation.

  30. 30.

    , & Functional role of extranucleosomal DNA and the entry site of the nucleosome in chromatin remodeling by ISW2. Mol. Cell. Biol. 24, 10047–10057 (2004).

  31. 31.

    et al. A 'loop recapture' mechanism for ACF-dependent nucleosome remodeling. Nat. Struct. Mol. Biol. 12, 683–690 (2005).

  32. 32.

    , , & Analysis of nucleosome repositioning by yeast ISWI and Chd1 chromatin remodeling complexes. J. Biol. Chem. 281, 16279–16288 (2006).

  33. 33.

    & Regulation of ISWI involves inhibitory modules antagonized by nucleosomal epitopes. Nature 492, 280–284 (2012). This work demonstrates that the ISWI ATPase is an intrinsically active DNA translocase that is regulated by 'inhibition of inhibition' of both ATPase activity and coupling.

  34. 34.

    et al. H2A histone-fold and DNA elements in nucleosome activate SWR1-mediated H2A.Z replacement in budding yeast. eLife 4, e06845 (2015). This work demonstrates that SWR1C interacts with nucleosomes at position SHL2 and that histone exchange requires DNA translocation.

  35. 35.

    et al. Regulation of DNA translocation efficiency within the chromatin remodeler RSC/Sth1 potentiates nucleosome sliding and ejection. Mol. Cell 62, 453–461 (2016). This study shows that nucleosome ejection by the Sth1 ATPase is achieved through the upregulation of DNA translocation efficiency, and that actin-related proteins are required by the remodeller RSC for nucleosome ejection.

  36. 36.

    , , & ATP-dependent histone octamer sliding mediated by the chromatin remodeling complex NURF. Cell 97, 833–842 (1999).

  37. 37.

    , , & Nucleosome movement by CHRAC and ISWI without disruption or trans-displacement of the histone octamer. Cell 97, 843–852 (1999). References 36 and 37 reveal the capacity of ISWI subfamily remodellers to perform nucleosome sliding.

  38. 38.

    et al. Nucleosome mobilization catalysed by the yeast SWI/SNF complex. Nature 400, 784–787 (1999). This work showed for the first time that SWI/SNF subfamily remodellers carry out nucleosome sliding.

  39. 39.

    , & SWI/SNF chromatin remodeling requires changes in DNA topology. Mol. Cell 7, 97–104 (2001).

  40. 40.

    & Dynamics of ATP-dependent chromatin assembly by ACF. Nature 418, 897–900 (2002).

  41. 41.

    , , & SWI/SNF unwraps, slides, and rewraps the nucleosome. Mol. Cell 11, 391–403 (2003).

  42. 42.

    et al. Reaction cycle of the yeast Isw2 chromatin remodeling complex. EMBO J. 23, 3836–3843 (2004).

  43. 43.

    , , , & Topography of the ISW2-nucleosome complex: insights into nucleosome spacing and chromatin remodeling. EMBO J. 23, 2092–2104 (2004).

  44. 44.

    , & Spatial contacts and nucleosome step movements induced by the NURF chromatin remodeling complex. J. Biol. Chem. 279, 39933–39941 (2004). References 43 and 44 define the binding of the ISWI subfamily remodellers to extranucleosomal DNA, and within the nucleosome two DNA helical turns from the dyad.

  45. 45.

    , & Chromatin remodelling: the industrial revolution of DNA around histones. Nat. Rev. Mol. Cell Biol. 7, 437–447 (2006).

  46. 46.

    , , & The chromatin-remodeling enzyme ACF is an ATP-dependent DNA length sensor that regulates nucleosome spacing. Nat. Struct. Mol. Biol. 13, 1078–1083 (2006).

  47. 47.

    , & Structure and mechanism of helicases and nucleic acid translocases. Annu. Rev. Biochem. 76, 23–50 (2007).

  48. 48.

    , , & The chromodomains of the Chd1 chromatin remodeler regulate DNA access to the ATPase motor. Mol. Cell 39, 711–723 (2010).

  49. 49.

    , , , & Structure of chromatin remodeler Swi2/Snf2 in the resting state. Nat. Struct. Mol. Biol. 23, 722–729 (2016).

  50. 50.

    , , , & Structure and regulation of the chromatin remodeller ISWI. Nature 540, 466–469 (2016). References 48–50 present the crystal structures of the Chd1, Snf2 and ISWI chromatin remodellers.

  51. 51.

    et al. ISWI remodelers slide nucleosomes with coordinated multi-base-pair entry steps and single-base-pair exit steps. Cell 152, 442–452 (2013).

  52. 52.

    , , , & Crystal structures of complexes of PcrA DNA helicase with a DNA substrate indicate an inchworm mechanism. Cell 97, 75–84 (1999).

  53. 53.

    , & Chromatin remodeling through directional DNA translocation from an internal nucleosomal site. Nat. Struct. Mol. Biol. 12, 747–755 (2005).

  54. 54.

    , & Histone octamer transfer by a chromatin-remodeling complex. Cell 96, 389–392 (1999). This was the first report of nucleosome ejection by SWI/SNF remodellers.

  55. 55.

    , , & Chromatin remodeling by ISW2 and SWI/SNF requires DNA translocation inside the nucleosome. Nat. Struct. Mol. Biol. 13, 339–346 (2006). References 53 and 55 demonstrate that DNA translocation occurs within the nucleosome.

  56. 56.

    et al. The SnAC domain of SWI/SNF is a histone anchor required for remodeling. Mol. Cell. Biol. 33, 360–370 (2013).

  57. 57.

    , & The INO80 ATP-dependent chromatin remodeling complex is a nucleosome spacing factor. Mol. Cell. Biol. 31, 662–673 (2011).

  58. 58.

    , , , & Extranucleosomal DNA binding directs nucleosome sliding by Chd1. Mol. Cell. Biol. 31, 4746–4759 (2011).

  59. 59.

    , & No need for a power stroke in ISWI-mediated nucleosome sliding. EMBO Rep. 14, 1092–1097 (2013).

  60. 60.

    , , & Histone H4 tail mediates allosteric regulation of nucleosome remodelling by linker DNA. Nature 512, 213–217 (2014).

  61. 61.

    , & ATP-dependent nucleosome disruption at a heat-shock promoter mediated by binding of GAGA transcription factor. Nature 367, 525–532 (1994).

  62. 62.

    , & GAL4 directs nucleosome sliding induced by NURF. EMBO J. 21, 1406–1413 (2002).

  63. 63.

    et al. The Chd1 chromatin remodeler can sense both entry and exit sides of the nucleosome. Nucleic Acids Res. 44, 7580–7591 (2016).

  64. 64.

    et al. The chromatin remodelling enzymes SNF2H and SNF2L position nucleosomes adjacent to CTCF and other transcription factors. PLoS Genet. 12, e1005940 (2016).

  65. 65.

    , , , & Critical role for the histone H4 N terminus in nucleosome remodeling by ISWI. Mol. Cell. Biol. 21, 875–883 (2001).

  66. 66.

    , , , & Histone tails modulate nucleosome mobility and regulate ATP-dependent nucleosome sliding by NURF. Proc. Natl Acad. Sci. USA 98, 14316–14321 (2001).

  67. 67.

    , & A critical epitope for substrate recognition by the nucleosome remodeling ATPase ISWI. Nucleic Acids Res. 30, 649–655 (2002). References 65–67 report the discovery and characterization of the activation of the ISWI remodeller by the histone H4 tail basic patch.

  68. 68.

    , & Two distinct mechanisms of chromatin interaction by the Isw2 chromatin remodeling complex in vivo. Mol. Cell. Biol. 25, 9165–9174 (2005).

  69. 69.

    , & Regulation of ISW2 by concerted action of histone H4 tail and extranucleosomal DNA. Mol. Cell. Biol. 26, 7388–7396 (2006).

  70. 70.

    et al. The histone H4 tail regulates the conformation of the ATP-binding pocket in the SNF2h chromatin remodeling enzyme. J. Mol. Biol. 426, 2034–2044 (2014).

  71. 71.

    , , & The ATPase domain of ISWI is an autonomous nucleosome remodeling machine. Nat. Struct. Mol. Biol. 20, 82–89 (2013).

  72. 72.

    et al. The chromatin remodeller ACF acts as a dimeric motor to space nucleosomes. Nature 462, 1016–1021 (2009).

  73. 73.

    & A nucleotide-driven switch regulates flanking DNA length sensing by a dimeric chromatin remodeler. Mol. Cell 57, 850–859 (2015).

  74. 74.

    , , & Structural analysis of the RSC chromatin-remodeling complex. Proc. Natl Acad. Sci. USA 99, 13477–13480 (2002).

  75. 75.

    , , , & Structural analysis of the yeast SWI/SNF chromatin remodeling complex. Nat. Struct. Biol. 10, 141–145 (2003).

  76. 76.

    , , & Structural studies of the human PBAF chromatin-remodeling complex. Structure 13, 267–275 (2005).

  77. 77.

    et al. Conformational flexibility in the chromatin remodeler RSC observed by electron microscopy and the orthogonal tilt reconstruction method. Proc. Natl Acad. Sci. USA 104, 4913–4918 (2007).

  78. 78.

    , & Acetylated histone tail peptides induce structural rearrangements in the RSC chromatin remodeling complex. J. Biol. Chem. 282, 20804–20808 (2007).

  79. 79.

    et al. Structure of a RSC-nucleosome complex and insights into chromatin remodeling. Nat. Struct. Mol. Biol. 15, 1272–1277 (2008).

  80. 80.

    et al. Architecture of the SWI/SNF-nucleosome complex. Mol. Cell. Biol. 28, 6010–6021 (2008).

  81. 81.

    , & Site-specific attachment of reporter compounds to recombinant histones. Methods Enzymol. 375, 211–228 (2004).

  82. 82.

    , & Chromatin remodeling by nucleosome disassembly in vitro. Proc. Natl Acad. Sci. USA 103, 3090–3093 (2006).

  83. 83.

    , , & Swi3p controls SWI/SNF assembly and ATP-dependent H2A-H2B displacement. Nat. Struct. Mol. Biol. 14, 540–547 (2007).

  84. 84.

    & The ATP-dependent remodeler RSC transfers histone dimers and octamers through the rapid formation of an unstable encounter intermediate. Biochemistry 49, 9882–9890 (2010).

  85. 85.

    Chromatin remodeling: insights and intrigue from single-molecule studies. Nat. Struct. Mol. Biol. 14, 989–996 (2007).

  86. 86.

    , & Nucleosome retention and the stochastic nature of promoter chromatin remodeling for transcription. Cell 133, 716–726 (2008).

  87. 87.

    et al. Nucleosomes can invade DNA territories occupied by their neighbors. Nat. Struct. Mol. Biol. 16, 151–158 (2009).

  88. 88.

    et al. SWI/SNF has intrinsic nucleosome disassembly activity that is dependent on adjacent nucleosomes. Mol. Cell 38, 590–602 (2010).

  89. 89.

    , , & Global regulation of H2A. Z localization by the INO80 chromatin-remodeling enzyme is essential for genome integrity. Cell 144, 200–213 (2011). This study demonstrates nucleosome editing by the remodeller INO80C and that INO80C prevents the mislocalization of H2A.Z outside of gene promoters.

  90. 90.

    , , & Involvement of actin-related proteins in ATP-dependent chromatin remodeling. Mol. Cell 12, 147–155 (2003).

  91. 91.

    et al. H3.3/H2A.Z double variant-containing nucleosomes mark 'nucleosome-free regions' of active promoters and other regulatory regions. Nat. Genet. 41, 941–945 (2009).

  92. 92.

    , , & A histone acetylation switch regulates H2A.Z deposition by the SWR-C remodeling enzyme. Science 340, 195–199 (2013).

  93. 93.

    et al. Chromatin dynamics and the RNA exosome function in concert to regulate transcriptional homeostasis. Cell Rep. 13, 1610–1622 (2015).

  94. 94.

    , & Genome-wide dynamics of Htz1, a histone H2A variant that poises repressed/basal promoters for activation through histone loss. Cell 123, 219–231 (2005).

  95. 95.

    et al. Histone variant H2A.Z marks the 5' ends of both active and inactive genes in euchromatin. Cell 123, 233–248 (2005).

  96. 96.

    et al. Swc2 is a widely conserved H2AZ-binding module essential for ATP-dependent histone exchange. Nat. Struct. Mol. Biol. 12, 1064–1071 (2005).

  97. 97.

    et al. The catalytic subunit of the SWR1 remodeler is a histone chaperone for the H2A.Z-H2B dimer. Mol. Cell 53, 498–505 (2014).

  98. 98.

    et al. Stepwise histone replacement by SWR1 requires dual activation with histone H2A. Z and canonical nucleosome. Cell 143, 725–736 (2010). This study describes the stepwise replacement of H2A with H2A.Z in nucleosomes by the remodeller SWR1C.

  99. 99.

    et al. Molecular architecture of the ATP-dependent chromatin-remodeling complex SWR1. Cell 154, 1220–1231 (2013).

  100. 100.

    et al. Structure and subunit topology of the INO80 chromatin remodeler and its nucleosome complex. Cell 154, 1207–1219 (2013).

  101. 101.

    et al. Structural analyses of the chromatin remodelling enzymes INO80-C and SWR-C. Nat. Commun. 6, 7108 (2015). References 99–101 present the latest structures of the remodellers INO80C and SWR1C.

  102. 102.

    et al. The HSA domain binds nuclear actin-related proteins to regulate chromatin-remodeling ATPases. Nat. Struct. Mol. Biol. 15, 469–476 (2008).

  103. 103.

    et al. Subunit organization of the human INO80 chromatin remodeling complex: an evolutionarily conserved core complex catalyzes ATP-dependent nucleosome remodeling. J. Biol. Chem. 286, 11283–11289 (2011).

  104. 104.

    , & Multiple modes of regulation of the human Ino80 SNF2 ATPase by subunits of the INO80 chromatin-remodeling complex. Proc. Natl Acad. Sci. USA 110, 20497–20502 (2013).

  105. 105.

    et al. Assembly of the Arp5 (actin-related protein) subunit involved in distinct INO80 chromatin remodeling activities. J. Biol. Chem. 290, 25700–25709 (2015).

  106. 106.

    , , & Synergy and antagonism in regulation of recombinant human INO80 chromatin remodeling complex. Nucleic Acids Res. 44, 8179–8188 (2016).

  107. 107.

    & Signals and combinatorial functions of histone modifications. Annu. Rev. Biochem. 80, 473–499 (2011).

  108. 108.

    & Chromatin remodeling: a marriage between two families? Bioessays 20, 771–780 (1998).

  109. 109.

    , , , & SWI/SNF binding to the HO promoter requires histone acetylation and stimulates TATA-binding protein recruitment. Mol. Cell. Biol. 26, 4095–4110 (2006).

  110. 110.

    et al. Histone H3 tail acetylation modulates ATP-dependent remodeling through multiple mechanisms. Nucleic Acids Res. 39, 8378–8391 (2011).

  111. 111.

    et al. Function and selectivity of bromodomains in anchoring chromatin-modifying complexes to promoter nucleosomes. Cell 111, 369–379 (2002).

  112. 112.

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

  113. 113.

    , & Structural basis of histone H4 recognition by p55. Genes Dev. 22, 1313–1318 (2008).

  114. 114.

    et al. Double chromodomains cooperate to recognize the methylated histone H3 tail. Nature 438, 1181–1185 (2005).

  115. 115.

    et al. Plant homeodomain (PHD) fingers of CHD4 are histone H3-binding modules with preference for unmodified H3K4 and methylated H3K9. J. Biol. Chem. 286, 11779–11791 (2011).

  116. 116.

    et al. Recognition of a mononucleosomal histone modification pattern by BPTF via multivalent interactions. Cell 145, 692–706 (2011).

  117. 117.

    et al. Molecular basis of histone tail recognition by human TIP5 PHD finger and bromodomain of the chromatin remodeling complex NoRC. Structure 23, 80–92 (2015).

  118. 118.

    & The bromodomain interaction module. FEBS Lett. 586, 2692–2704 (2012).

  119. 119.

    Chromatin remodeling enzymes: taming the machines: third in review series on chromatin dynamics. EMBO Rep. 3, 319–322 (2002).

  120. 120.

    et al. Methylation of histone H3 K4 mediates association of the Isw1p ATPase with chromatin. Mol. Cell 12, 1325–1332 (2003).

  121. 121.

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

  122. 122.

    et al. Chromatin remodelers Isw1 and Chd1 maintain chromatin structure during transcription by preventing histone exchange. Nat. Struct. Mol. Biol. 19, 884–892 (2012).

  123. 123.

    et al. Human but not yeast CHD1 binds directly and selectively to histone H3 methylated at lysine 4 via its tandem chromodomains. J. Biol. Chem. 280, 41789–41792 (2005).

  124. 124.

    et al. The PHD and chromo domains regulate the ATPase activity of the human chromatin remodeler CHD4. J. Mol. Biol. 422, 3–17 (2012).

  125. 125.

    , & Histone modifications influence the action of Snf2 family remodelling enzymes by different mechanisms. J. Mol. Biol. 374, 563–579 (2007).

  126. 126.

    , , , & A cooperative activation loop among SWI/SNF, gamma-H2AX and H3 acetylation for DNA double-strand break repair. EMBO J. 29, 1434–1445 (2010).

  127. 127.

    & SWI/SNF recruitment to a DNA double-strand break by the NuA4 and Gcn5 histone acetyltransferases. DNA Repair (Amst.) 30, 38–45 (2015).

  128. 128.

    , , , & Gcn5 regulates the dissociation of SWI/SNF from chromatin by acetylation of Swi2/Snf2. Genes Dev. 24, 2766–2771 (2010).

  129. 129.

    et al. Swi/Snf dynamics on stress-responsive genes is governed by competitive bromodomain interactions. Genes Dev. 28, 2314–2330 (2014).

  130. 130.

    et al. Autoregulation of the rsc4 tandem bromodomain by gcn5 acetylation. Mol. Cell 27, 817–828 (2007).

  131. 131.

    et al. NuA4-dependent acetylation of nucleosomal histones H4 and H2A directly stimulates incorporation of H2A.Z by the SWR1 complex. J. Biol. Chem. 285, 15966–15977 (2010).

  132. 132.

    , & Chromatin remodeling by imitation switch (ISWI) class ATP-dependent remodelers is stimulated by histone variant H2A.Z. J. Biol. Chem. 285, 4645–4651 (2010). This work was the first to show a regulatory role for H2A.Z in nucleosome remodelling by ISWI.

  133. 133.

    , , & Modulation of ISWI function by site-specific histone acetylation. EMBO Rep. 3, 242–247 (2002). This work was the first to demonstrate that chromatin remodellers can be regulated by a histone modification.

  134. 134.

    et al. Histone H4-K16 acetylation controls chromatin structure and protein interactions. Science 311, 844–847 (2006).

  135. 135.

    et al. ISWI remodelling of physiological chromatin fibres acetylated at lysine 16 of histone H4. PLoS ONE 9, e88411 (2014).

  136. 136.

    et al. A method for genetically installing site-specific acetylation in recombinant histones defines the effects of H3 K56 acetylation. Mol. Cell 36, 153–163 (2009).

  137. 137.

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

  138. 138.

    , , & DNA looping facilitates targeting of a chromatin remodeling enzyme. Mol. Cell 50, 93–103 (2013).

  139. 139.

    & Remodeling the chromatin structure of a nucleosome array by transcription factor-targeted trans-displacement of histones. EMBO J. 15, 4702–4712 (1996).

  140. 140.

    , , & Activation domains drive nucleosome eviction by SWI/SNF. EMBO J. 26, 730–740 (2007).

  141. 141.

    , , & Recruitment of the SWI/SNF chromatin remodeling complex by transcriptional activators. Genes Dev. 13, 2369–2374 (1999). References 139–141 present initial evidence that transcription activators can regulate chromatin remodelling.

  142. 142.

    et al. Dynamic regulation of transcription factors by nucleosome remodeling. eLife 4, e06249 (2015).

  143. 143.

    , , , & UV-induced association of the CSB remodeling protein with chromatin requires ATP-dependent relief of N-terminal autorepression. Mol. Cell 37, 235–246 (2010).

  144. 144.

    et al. Regulation of the Rhp26ERCC6/CSB chromatin remodeler by a novel conserved leucine latch motif. Proc. Natl Acad. Sci. USA 111, 18566–18571 (2014).

  145. 145.

    & Direct interactions promote eviction of the Sir3 heterochromatin protein by the SWI/SNF chromatin remodeling enzyme. Proc. Natl Acad. Sci. USA 111, 17827–17832 (2014).

  146. 146.

    , , & SWI/SNF mediates polycomb eviction and epigenetic reprogramming of the INK4b-ARF- INK4a locus. Mol. Cell. Biol. 28, 3457–3464 (2008).

  147. 147.

    et al. esBAF facilitates pluripotency by conditioning the genome for LIF/STAT3 signalling and by regulating polycomb function. Nat. Cell Biol. 13, 903–913 (2011).

  148. 148.

    & Histone exchange, chromatin structure and the regulation of transcription. Nat. Rev. Mol. Cell Biol. 16, 178–189 (2015).

  149. 149.

    & Nucleosome disassembly during human non-homologous end joining followed by concerted HIRA- and CAF-1-dependent reassembly. eLife 5, e15129 (2016).

  150. 150.

    , , & The chromatin remodelers RSC and ISW1 display functional and chromatin-based promoter antagonism. eLife 4, e06073 (2015).

  151. 151.

    , , & The ISW1 and CHD1 ATP-dependent chromatin remodelers compete to set nucleosome spacing in vivo. Nucleic Acids Res. 44, 4625–4635 (2016).

  152. 152.

    , & The structure of NoRC-associated RNA is crucial for targeting the chromatin remodelling complex NoRC to the nucleolus. EMBO Rep. 9, 774–780 (2008).

  153. 153.

    et al. The ISWI chromatin remodeler organizes the hsromega ncRNA-containing omega speckle nuclear compartments. PLoS Genet. 7, e1002096 (2011).

  154. 154.

    et al. The long noncoding RNA SChLAP1 promotes aggressive prostate cancer and antagonizes the SWI/SNF complex. Nat. Genet. 45, 1392–1398 (2013).

  155. 155.

    et al. A long noncoding RNA protects the heart from pathological hypertrophy. Nature 514, 102–106 (2014).

  156. 156.

    , , , & Daxx is an H3.3-specific histone chaperone and cooperates with ATRX in replication-independent chromatin assembly at telomeres. Proc. Natl Acad. Sci. USA 107, 14075–14080 (2010).

  157. 157.

    & SnapShot: chromatin remodeling complexes. Cell 129, 632 (2007).

  158. 158.

    & Chromatin regulatory mechanisms in pluripotency. Annu. Rev. Cell Dev. Biol. 26, 503–532 (2010).

  159. 159.

    et al. ATR-X syndrome protein targets tandem repeats and influences allele-specific expression in a size-dependent manner. Cell 143, 367–378 (2010).

  160. 160.

    et al. A Rad26-Def1 complex coordinates repair and RNA pol II proteolysis in response to DNA damage. Nature 415, 929–933 (2002).

  161. 161.

    et al. ATP-dependent chromatin remodeling by the Cockayne syndrome B DNA repair-transcription-coupling factor. Mol. Cell. Biol. 20, 7643–7653 (2000).

  162. 162.

    & Multiple roles for ISWI in transcription, chromosome organization and DNA replication. Biochim. Biophys. Acta 1677, 113–119 (2004).

  163. 163.

    & SnapShot: chromatin remodeling: ISWI. Cell 144, 453–453.e1 (2011).

  164. 164.

    et al. Crystal structure and functional analysis of a nucleosome recognition module of the remodeling factor ISWI. Mol. Cell 12, 449–460 (2003).

  165. 165.

    , & The SANT domain: a unique histone-tail-binding module? Nat. Rev. Mol. Cell Biol. 5, 158–163 (2004).

  166. 166.

    & Domain architecture of the catalytic subunit in the ISW2-nucleosome complex. Mol. Cell. Biol. 27, 8306–8317 (2007).

  167. 167.

    et al. Yeast Isw1p forms two separable complexes in vivo. Mol. Cell. Biol. 23, 80–91 (2003).

  168. 168.

    et al. Dual functions of largest NURF subunit NURF301 in nucleosome sliding and transcription factor interactions. Mol. Cell 8, 531–543 (2001).

  169. 169.

    , , , & TRF2 associates with DREF and directs promoter-selective gene expression in Drosophila. Nature 420, 439–445 (2002).

  170. 170.

    , , & The chromo domain protein chd1p from budding yeast is an ATP-dependent chromatin-modifying factor. EMBO J. 19, 2323–2331 (2000).

  171. 171.

    & Novel Mi-2 related ATP-dependent chromatin remodelers. Epigenetics 4, 209–211 (2009).

  172. 172.

    , , , & The DNA-binding domain of the Chd1 chromatin-remodelling enzyme contains SANT and SLIDE domains. EMBO J. 30, 2596–2609 (2011).

  173. 173.

    & The human Mi-2/NuRD complex and gene regulation. Oncogene 26, 5433–5438 (2007).

  174. 174.

    & CHD chromatin remodelers and the transcription cycle. Transcription 2, 244–253 (2011).

  175. 175.

    et al. CHD1 motor protein is required for deposition of histone variant H3.3 into chromatin in vivo. Science 317, 1087–1090 (2007).

  176. 176.

    , & The NuRD architecture. Cell. Mol. Life Sci. 70, 3513–3524 (2013).

  177. 177.

    & Composition and functional specificity of SWI2/SNF2 class chromatin remodeling complexes. Biochim. Biophys. Acta 1681, 59–73 (2005).

  178. 178.

    , & SnapShot: chromatin remodeling: SWI/SNF. Cell 144, 310.e1 (2011).

  179. 179.

    et al. Structure of an actin-related subcomplex of the SWI/SNF chromatin remodeler. Proc. Natl Acad. Sci. USA 110, 3345–3350 (2013). This work presented the first structure of an ARP module bound to a remodeller HSA domain.

  180. 180.

    & Chromatin remodelling beyond transcription: the INO80 and SWR1 complexes. Nat. Rev. Mol. Cell Biol. 10, 373–384 (2009).

  181. 181.

    & SnapShot: chromatin remodeling: INO80 and SWR1. Cell 144, 158–158.e2 (2011).

  182. 182.

    & RVB1/RVB2: running rings around molecular biology. Mol. Cell 34, 521–533 (2009).

  183. 183.

    et al. Eaf1 is the platform for NuA4 molecular assembly that evolutionarily links chromatin acetylation to ATP-dependent exchange of histone H2A variants. Mol. Cell. Biol. 28, 2257–2270 (2008).

  184. 184.

    et al. Crystal structure of a nuclear actin ternary complex. Proc. Natl Acad. Sci. USA 113, 8985–8990 (2016).

  185. 185.

    et al. EP400 deposits H3.3 into promoters and enhancers during gene activation. Mol. Cell 61, 27–38 (2016).

  186. 186.

    , & Interplay between Ino80 and Swr1 chromatin remodeling enzymes regulates cell cycle checkpoint adaptation in response to DNA damage. Genes Dev. 20, 2437–2449 (2006).

  187. 187.

    , & Distinct roles for SWR1 and INO80 chromatin remodeling complexes at chromosomal double-strand breaks. EMBO J. 26, 4113–4125 (2007).

  188. 188.

    et al. YY1 functions with INO80 to activate transcription. Nat. Struct. Mol. Biol. 14, 872–874 (2007).

  189. 189.

    et al. A YY1-INO80 complex regulates genomic stability through homologous recombination-based repair. Nat. Struct. Mol. Biol. 14, 1165–1172 (2007).

  190. 190.

    , , , & Crystal structure of the nucleosome core particle at 2.8 A resolution. Nature 389, 251–260 (1997).

  191. 191.

    , , , & Solvent mediated interactions in the structure of the nucleosome core particle at 1.9 a resolution. J. Mol. Biol. 319, 1097–1113 (2002).

  192. 192.

    , & Distortion of histone octamer core promotes nucleosome mobilization by a chromatin remodeler. Science 355, eaaa3761 (2017).

  193. 193.

    , , , & Mechanism of chromatin remodeling revealed by the Snf2−nucleosome structure. Nature 544, 440–445 (2017).

  194. 194.

    et al. Concerted regulation of ISWI by an autoinhibitory domain and the H4 tail N-terminal tail. eLife 6, e21477 (2017).

  195. 195.

    et al. Interdomain communication of the Chd1 chromatin remodeler across the DNA gyres of the nucleosome. Mol. Cell 65, 447–459 (2017).

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Acknowledgements

This work was supported by the Howard Hughes Medical Institute (HHMI) (C.R.C. and B.R.C.), the US National Institutes of Health (NIH) (GM60415 to B.R.C.; GM054096 and GM049650 to C.L.P.).

Author information

Affiliations

  1. Howard Hughes Medical Institute and Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, Utah 84112, USA.

    • Cedric R. Clapier
    •  & Bradley R. Cairns
  2. Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, Utah 84112, USA.

    • Janet Iwasa
  3. Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA.

    • Craig L. Peterson

Authors

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Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Bradley R. Cairns or Craig L. Peterson.

Supplementary information

PDF files

  1. 1.

    Supplementary information S1 (figure)

    The composition of each subfamily of chromatin remodellers in Saccharomyces cerevisiae.

  2. 2.

    Supplementary information S2 (figure)

    Structures of chromatin remodellers.

  3. 3.

    Supplementary information S8 (box)

    Actin and actin-related proteins

Videos

  1. 1.

    Supplementary Movie 3

    Monomeric DNA helicases and chromatin remodellers share a common mode of translocation, involving a protein motor core formed by two RecA-like lobes (shown in light and dark orange) which bind the same strand of DNA with one lobe slightly ahead of the other. These lobes sequentially bind and release DNA, enabling an 'inchworming' mechanism of unidirectional movement in the 3′ to 5′ direction along the tracking strand. In order to perceive how this property is applied to the nucleosome, we change perspective and hold the translocating enzyme in a fixed position. The DNA then appears to be pumped by the enzyme, and undergoes rotation during translocation. We now depict the RecA-like lobes as mittens that reciprocally move, grip and release from the DNA backbone. The physical step size of 1 base pair per ATP hydrolysis depicted here is based on crystal structures and biophysical measurements of translocation (which are 1 to 2 bp) by chromatin remodelling ATPases and related helicases and translocases.

  2. 2.

    Supplementary Movie 4

    This animation starts by depicting both the protein and DNA components of the nucleosome, which is the fundamental unit of chromatin structure in eukaryotes. The eight histone proteins are shown in green, and the DNA helix in blue and white. The canonical nucleosome core particle consists of 147 base pairs of DNA wrapped in 1.67 left-handed superhelical turns around a histone octamer, though in this depiction the DNA is extended. The nucleosome has a two-fold rotational symmetry along a feature called the dyad axis, depicted here with a grey stippled bar. By making the DNA semi-opaque, the thirteen histone-DNA contacts can be visualized (flashing white, and then staying blue) to form a positively-charged staircase along the surface of the octamer, upon which the negatively-charged DNA is wrapped. By unwrapping the DNA, the canonical octamer is revealed, and subsequently disassembled into the central H3-H4 tetramer (light green proteins) capped on each end by an H2A-H2B dimer (darker green proteins). Following octamer reassembly, the staircase of histone-DNA contacts is again revisited, and the DNA re-wrapped along that staircase to form the nucleosome.

  3. 3.

    Supplementary Movie 5

    Here we depict how chromatin remodellers can conduct nucleosome sliding via monotonous DNA translocation. First, we show a canonical nucleosome, and depict the DNA much shorter on one side, to help illustrate subsequent DNA movement and extension. Here, this canonical nucleosome is bound and fully enveloped by RSC, a SWI/SNF subfamily remodeller from yeast, which has a large pocket of nearly perfect nucleosome dimensions. Within RSC, the two orange RecA-like lobes bind to the DNA at a fixed position within the nucleosome, about two turns from the dyad axis. From this fixed position, the lobes perform directional DNA translocation by pulling in DNA from the proximal side of the nucleosome and pumping it toward the distal side. Here, the lobes function like DNA-grabbing mittens, which undergo a cycle of inchworming along the DNA backbone, sequentially grabbing and releasing the DNA, translocating one base pair of DNA per ATP hydrolysis. This is a simplified version, termed monotonous, in which the DNA at the entry site moves in concert with DNA at the exit site, one base pair at a time. A more sophisticated depiction involving sequential movement, first on the distal size and then on the proximal side, is shown in the next animation.

  4. 4.

    Supplementary Movie 6

    Here we depict how chromatin remodellers can conduct nucleosome sliding via sequential (or discontinuous) DNA translocation. First, we show a canonical nucleosome, and depict the DNA much shorter on one side, to help illustrate subsequent DNA movement and extension. Next, the two orange RecA-like lobes, present on all remodellers, bind to nucleosomal DNA at a fixed position, two helical turns from the dyad axis and perform directional DNA translocation by pulling in DNA from the proximal side of the nucleosome and pumping it toward the distal side. Here, the lobes function like DNA-grabbing mittens, which undergo a cycle of inchworming along the DNA backbone, sequentially grabbing and releasing the DNA, translocating one base pair of DNA per ATP hydrolysis. Translocation creates DNA torsion and translational tension on both sides of the mittens – which in this animation, is resolved in 3 base pair increments, in two sequential steps – as has been shown in the remodeller ISWI. On the distal side, the extra DNA can propagate in a wave-like manner toward the distal exit side of the nucleosome by diffusion, breaking histone-DNA contacts as it propagates (depicted by flashing lights), and extending the DNA on the distal side. Next, on the proximal side, translocation also breaks histone-DNA contacts (also depicted as flashing lights), drawing DNA from the proximal linker into the nucleosome. The result is histone octamer displacement, generically referred to as nucleosome sliding.

  5. 5.

    Supplementary Movie 7

    We depict here the ISWI ATPase bound to a fragment of the Acf1 protein in an unfolded state. The ISWI remodeller contains two RecA-like lobes, which comprise the DNA translocating motor, as well as three remarkable regulatory domains: AutoN, NegC and HSS. Two of these domains, AutoN and NegC, have autoinhibitory functions, and are therefore depicted in red under conditions where they inhibit ISWI, for example in the folded structure in the absence of the nucleosome. The order of domain interaction with the nucleosome is not known, but for depiction here we display the initial binding of ISWI RecA-like lobes to the nucleosome, two-turns from the dyad, followed by the binding of the HSS domain to the linker DNA on the proximal side. The presence of the H4 tail (in light green) releases AutoN inhibition (notice the color change) via a competition mechanism, which increases the ATPase activity. Concomitantly, the release of the NegC inhibition (also note the color change) and restoration of coupling, occurs via change of conformation due to HSS binding the DNA, seen on the reverse angle. Once released from its intrinsic inhibitions, the RecA-like lobes perform DNA translocation, pulling DNA and causing tension. On the distal side, this tension is resolved by DNA wave propagation. On the proximal side, the tension is constrained between the lobes and the HSS domain which is resolved by the HSS releasing from the linker DNA, allowing DNA to be drawn into the nucleosome before rebinding. This cycle results in the displacement of the histone octamer relative to the DNA, termed nucleosome sliding. Iterations of this cycle draw the adjacent nucleosome closer and closer, progressively shortening the linker DNA, until the adjacent nucleosome interferes with the binding of the HSS domain by steric hindrance. When the HSS can no longer rebind linker DNA, ISWI changes to a conformation in which HSS fails to antagonize the NegC domain and the H4 tail stops competing with AutoN, resulting in the cessation of DNA translocation and the release of ISWI from the nucleosome. Thus, the HSS functions as a 'molecular ruler' leaving the adjacent nucleosome at a fixed distance from the substrate nucleosome (termed nucleosome spacing). Sequential application of this mechanism by one or more ISWI/ACF complexes (as depicted) occurring on all nucleosomes on the template produces an array that results in all the nucleosomes being the same distance apart.

  6. 6.

    Supplementary Movie 9

    In addition to the RecA-like lobes which comprise the DNA translocating motor, the SWI/SNF remodeller ATPase subunit contains an HSA domain, which binds a heterodimer of the Actin-Related Proteins, Arp7 and Arp9. The HSA region folds back and interacts with one of the RecA-like lobes. The SWI/SNF motor subunit binds to the nucleosome two helical turns from the dyad and performs DNA translocation through an inchworming mechanism, drawing in DNA from the proximal linker and pumping it towards the distal linker. Here, the flashing lights depict the breakage and reformation of histone-DNA contacts. This results in the displacement of the histone octamer relative to the DNA, termed nucleosome sliding. Binding of the Actin-Related Proteins to the HSA domain greatly improves the efficiency of DNA translocation. Efficient and forceful DNA translocation result in the rupture of several histone-DNA contacts, destabilizing the octamer, and leading to nucleosome ejection.

  7. 7.

    Supplementary Movie 10

    Beyond the RecA-like lobes (shown in orange), the SWR1C histone exchanger motor subunit (termed Swr1) contains an HSA domain which binds the Arp4 and Actin heterodimer, as well as a N-terminal domain for interaction with an H2A.Z variant-H2B dimer. Swr1 binds two helical turns from the dyad, and its N-terminus interacts with an H2A.Z variant-H2B dimer (shown in yellow-dark green), which stimulates Swr1 ATPase activity and DNA translocation. The SWR1C exchanger apparently does not allow translocated DNA to pass to the distal side of the nucleosome, perhaps due to the presence of a domain or protein that prevents additional DNA movement (shown in dark blue). By this model, only the histone-DNA contacts located on the proximal side of the nucleosome are destabilized, promoting the removal of a canonical H2A-H2B dimer and the loading of the H2A.Z variant-H2B dimer. Histone-DNA contacts are then restored by the DNA wrapping onto the newly-installed histone contact staircase (shown by flashing lights during re-wrapping), resulting in dimer replacement without any change in the translational position of the nucleosome.

Glossary

Replisome

A large protein complex that carries out the DNA replication process, from the unwinding of double-stranded DNA to strand duplication by DNA synthesis.

Histone chaperones

Proteins that bind to free histones, prevent histone aggregation and that can promote either nucleosome assembly or nucleosome disassembly.

Canonical histones

The four core histones (H2A, H2B, H3 and H4) that are most commonly assembled into nucleosomes during replication and that constitute almost all of the nucleosomes across the genome.

Histone variants

Differ by a few amino acids from canonical histones and are expressed at low-to-moderate levels and typically inserted into nucleosomes independently of replication; they create specific chromatin regions and functions.

RecA-like lobes

Protein domains of helicases and remodellers, similar in structure and sequence to the ATPase domain of the Escherichia coli DNA-binding protein RecA.

DNA twist

A measure of the extent of helical winding of the DNA strands around each other, along their common axis. Often expressed as the number of base pairs of DNA per helical turn in B-form DNA.

Persistence length

A mechanical property of polymer stiffness, which for DNA is approximately 100 bp.

Nucleosome dyad

A pseudo-two-fold symmetry element of the nucleosome core particle.

Gyre

In the context of a nucleosome, refers to one DNA wrap around the surface of the octamer.

DNA translocation efficiency

Quantified by measuring coupling, it describes the amount of DNA that is translocated per ATP hydrolysis and/or the probability that the enzyme conducts a DNA translocation step per ATP hydrolysis cycle.

Hexasome

Nucleosome that lacks one histone H2A–H2B dimer.

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DOI

https://doi.org/10.1038/nrm.2017.26

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