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  • Review Article
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Mechanisms of action and regulation of ATP-dependent chromatin-remodelling complexes

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.

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.

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Figure 1: Functions and domain organization of chromatin remodellers.
Figure 2: Model of the regulation of DNA translocation leading to precise nucleosome spacing by ISWI subfamily remodellers.
Figure 3: Models of nucleosome ejection by SWI/SNF subfamily remodellers.
Figure 4: Model of histone exchange by the remodeller SWR1C.
Figure 5: The hourglass model of chromatin remodelling.

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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.).

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

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Supplementary information

Supplementary information S1 (figure)

The composition of each subfamily of chromatin remodellers in Saccharomyces cerevisiae. (PDF 3212 kb)

Supplementary information S2 (figure)

Structures of chromatin remodellers. (PDF 1600 kb)

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. (MOV 16505 kb)

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. (MOV 30833 kb)

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. (MOV 23873 kb)

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. (MOV 44556 kb)

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. (MOV 38974 kb)

Supplementary information S8 (box)

Actin and actin-related proteins (PDF 149 kb)

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. (MOV 48695 kb)

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. (MOV 12977 kb)

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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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Clapier, C., Iwasa, J., Cairns, B. et al. Mechanisms of action and regulation of ATP-dependent chromatin-remodelling complexes. Nat Rev Mol Cell Biol 18, 407–422 (2017). https://doi.org/10.1038/nrm.2017.26

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