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

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.

Figure 1.. Functions and domain organization of chromatin remodellers.

a. Functional classification of remodellers. The ATPase–translocase subunit of all remodellers is depicted in pink; additional subunits are depicted in green (imitation switch(ISWI) and chromodomain helicase DNA-binding(CHD)), brown (switch/sucrose non-fermentable (SWI/SNF)) and blue (INO80). Nucleosome assembly: Particular ISWI and CHD subfamily remodellers participate in the random deposition of histones, the maturation of nucleosomes and their spacing. Chromatin access: Primarily SWI/SNF subfamily remodellers alter chromatin by repositioning nucleosomes, ejecting octamers or evicting histone dimers. Nucleosome editing: Remodellers of the INO80 subfamily (INO80C or Swr1 complex (SWR1C)) change nucleosome composition by exchanging canonical and variant histones, for example installing H2A.Z variants (yellow). We note that this functional classification is a simplification, as INO80C, the ISWI remodeller nucleosome remodelling factor (NURF) and certain CHD remodellers can promote chromatin access. b. Domain organization of remodeller subfamilies. The ATPase–translocase domain (Tr) of all the remodellers is sufficient to carry out DNA translocation. It is comprised of two RecA-like lobes (lobe 1 and lobe 2, which are separated by a short or long (such as in the INO80 subfamily) insertion (grey)). Remodellers can be classified into four subfamilies based on the length and function of the insertion and on their domain organization. c. ‘Inchworming’ mechanism of DNA translocation. An ATP binding–hydrolysis-dependent conformational cycle of the RecA-like lobes (‘mittens’) drives DNA translocation. Mittens are depicted closed when lobes have high affinity for DNA and open when lobes have low affinity for DNA (see also Supplementary information S3 (movie)). Although the DNA can be double stranded, only the tracking strand of DNA is depicted, along which the lobes move in the 3’–5’ direction (validated by single-stranded DNA studies). Steps are depicted as sequential, but they may be concerted, and a similar model with mitten/lobe 1 being stationary is equally supported. The yellow arrows represent remodeller movement; the green arrow represents DNA translocation. The precise step in which inorganic phosphate (Pi) is released is not known. NegC* is a region with structural similarity to the ISWI negatice regulator of coupling (NegC) domain. AutoN, autoinhibitory N-terminal; Bromo, bromodomain; CHD, chromodomain; DBD, DNA-binding domain; HSA, helicase/SANT-associated; HSS, HAND-SANT-SLIDE; SnAC, Snf2 ATP coupling. Part c is adapted from by REF. , Cell Press.

Figure 2.. Model of regulation of DNA translocation leading to precise nucleosome spacing by ISWI subfamily remodellers.

a. The nucleosome is shown with the left-handed wrapping of DNA around the histone octamer (grey transparent cylinder). The DNA colour changes from light green to dark green when passing the nucleosome dyad (from the proximal side to the distal side), to distinguish the second gyre [G]. The location where a remodeller ATPase–translocase (Tr) domain will bind on the nucleosome, as well as one H4 tail, is also depicted. A red circle serves as a reference point to trace DNA translocation. b. Schematic of the domain architecture of Drosophila melanogaster imitation switch (ISWI). Regulation of D. melanogaster ISWI: in the left-hand diagram, the autoinhibitory N-terminal (AutoN) and negative regulator of coupling (NegC) domains inhibit the ATPase activity and coupling of the translocase domain, respectively, thus inactivating DNA translocation. In the right-hand diagram, ISWI is activated by a double ‘inhibition of inhibition’: by the Arg17–Arg19 patch of the histone H4 tail and by linker DNA, which antagonize AutoN and NegC, thereby increasing ATPase and coupling, respectively, and activating DNA translocation. c. Precise spacing of nucleosomes by ISWI subfamily remodellers. The ISWI remodeller interacts with the nucleosome two DNA helical turns away from the dyad via its ATPase–translocase domain (Tr) and is anchored to the surface of the octamer by a histone-binsing domain (HBD). The H4 tail binds to the remodeller, releasing AutoN inhibition and activating ATPase activity. In parallel, the HAND-SANT-SLIDE (HSS) domain binds to linker DNA, releasing NegC inhibition and reinstating efficient coupling (State 1). The translocase domain translocates 3bp of DNA along the surface of the nucleosome (State 1 to State 2), generating DNA tension (orange) on both the proximal and the distal sides of the translocase domain, owing to the lack and excess of DNA, respectively (State 2). On the distal side, DNA tension is resolved (restoring green DNA colour) by one-dimensional diffusion of the 3bp of excess DNA (implemented as three 1bp steps), which moves around the distal side (2^nd half) of the nucleosome in the form of a small wave, and then resolves in the distal linker (State 2 to State 3). On the proximal side, DNA tension is resolved by DNA from the proximal linker entering the nucleosome, 3bp at a time, which requires the release of the HSS binding (State 3 to State 4). Consequently, the adjacent nucleosome approaches by 3bp (State 4) and the HSS re-binds linker DNA in its new position (State 5). This process is reiterated, resulting progressive approach of the adjacent nucleosome (State 5 to State 6), until the approaching octamer prevents the HSS from re-binding the linker DNA, thereby reinstating inhibition by NegC (State 6). DNA translocation then ceases, and the remodeller is released from the nucleosome (not shown), setting a precise inter-nucleosome distance. Multiple occurrences of this process result in nucleosome arrays with precise, regular spacing (Supplementary information S7 (movie)).

Figure 3.. Models of nucleosome ejection by SWI/SNF subfamily remodellers.

a. Regulation of DNA translocation leading to nucleosome ejection by switch/sucrose non-fermentable (SWI/SNF) subfamily remodellers. The actin-related protein (ARP) module regulates both the ATPase and the coupling activities of the ATPase-translocase domain (Tr), which interacts with the nucleosome two helical turns away from the dyad (State 1), anchors to the surface of the octamer via a histone-binding domain (HBD) and translocates 1–2 bp of DNA along the surface of the nucleosome (State 1 to State 2), thereby generating DNA tension on both the proximal and the distal sides of the translocase domain. Low to moderate ATPase activity and coupling leads to weak DNA translocation and low DNA tension (orange, State2a) that are resolved by sliding (restoring green DNA colour, State 3a). Continued DNA translocation results in continued sliding, the progressive displacement of the histone octamer with respect to the DNA (State 4a). Alternatively, SWI/SNF can generate high coupling (by the helicase/SANT-associated (HSA)-Arp7-Arp9 module) and high ATPase activity (by post-HSA), leading to strong DNA translocation and high DNA tension and disruption of histone-DNA contacts (red, State 2b), which results in histone ejection (State 3b; see Supplementary information S9 (movie)). b. Nucleosome ejection by spooling during remodelling by SWI/SNF subfamily remodellers. As shown in part a, the ATPase–translocase domain of the SWI/SNF subfamily remodellers can generate low-to-moderate DNA tension (State 1 to State 2) that is resolved by sliding. By iterations, continued DNA translocation and sliding lead to the approach of an adjacent octamer (State 3) that ultimately collides with the remodeller-bound nucleosome, resulting in the DNA being peeled of the adjacent octamer (State 4) and eventually in the ejection of the adjacent nucleosome by ‘spooling’ (State 5).

Figure 3.. Models of nucleosome ejection by SWI/SNF subfamily remodellers.

a. Regulation of DNA translocation leading to nucleosome ejection by switch/sucrose non-fermentable (SWI/SNF) subfamily remodellers. The actin-related protein (ARP) module regulates both the ATPase and the coupling activities of the ATPase-translocase domain (Tr), which interacts with the nucleosome two helical turns away from the dyad (State 1), anchors to the surface of the octamer via a histone-binding domain (HBD) and translocates 1–2 bp of DNA along the surface of the nucleosome (State 1 to State 2), thereby generating DNA tension on both the proximal and the distal sides of the translocase domain. Low to moderate ATPase activity and coupling leads to weak DNA translocation and low DNA tension (orange, State2a) that are resolved by sliding (restoring green DNA colour, State 3a). Continued DNA translocation results in continued sliding, the progressive displacement of the histone octamer with respect to the DNA (State 4a). Alternatively, SWI/SNF can generate high coupling (by the helicase/SANT-associated (HSA)-Arp7-Arp9 module) and high ATPase activity (by post-HSA), leading to strong DNA translocation and high DNA tension and disruption of histone-DNA contacts (red, State 2b), which results in histone ejection (State 3b; see Supplementary information S9 (movie)). b. Nucleosome ejection by spooling during remodelling by SWI/SNF subfamily remodellers. As shown in part a, the ATPase–translocase domain of the SWI/SNF subfamily remodellers can generate low-to-moderate DNA tension (State 1 to State 2) that is resolved by sliding. By iterations, continued DNA translocation and sliding lead to the approach of an adjacent octamer (State 3) that ultimately collides with the remodeller-bound nucleosome, resulting in the DNA being peeled of the adjacent octamer (State 4) and eventually in the ejection of the adjacent nucleosome by ‘spooling’ (State 5).

Figure 4.. Model of histone exchange by the remodeller SWR1C.

As in the case of imitation switch (ISWI) and switch/sucrose non-fermentable (SWI/SNF) subfamilies, the ATPase–translocase domain (Tr) of the yeast INO80 subfamily remodeller Swr1 complex (SWR1C) interacts with a nucleosome two helical turns away from the dyad (State 1), is anchored to the surface of the octamer via a histone-binding domain (HBD) and strongly translocates 1–2 bp of DNA at the surface of the nucleosome (State 1 to State 2), thereby generating high DNA tension (red DNA, State 2). On the distal side, resolution of DNA tension by DNA propagation may be prevented by the binding of the HBD (State 3). On the proximal side, DNA tension is resolved by the rupture of several upstream histone–DNA contacts (restoring green DNA colour, State 3), allowing the release of one canonical H2A–H2B dimer and the loading of a variant H2AZ–H2B dimer assisted by the Swc2 and/or Swr1 subunits (State 3 to State 4). Histone-DNA contacts are restored following the histone exchange (State 5; see Supplementary information S10 (movie)).

Figure 5.

The hourglass model of chromatin remodelling. Remodeller diversity (top) serves a variety of nucleosomal processes (bottom), but all might funnel through a unifying mechanism: an ATPase (‘motor’) subunit that is anchored to the histone octamer two helical turns away from the dyad that carries out DNA translocation (centre). At the top of the hourglass, the compositional diversity of remodellers enables specific interactions with particular transcription factors and/or histone modifications to specify targeting. The funnel depicts the implementation of ATP-dependent DNA translocation by the translocase (Tr) domain from a fixed location at the nucleosome, anchored by a histone-binding domain (HBD). At the bottom of the hourglass, the various nucleosome remodelling outcomes are depicted (assembly, access or editing), which are achieved through separate processes. Each process involves particular regulatory domains and/or proteins (blue boxes) on each remodeller, and their interactions with specific transcription factors and chromatin features, such as histone modifications, variants and linker DNA (green boxes). ARPs, actin-related proteins; AutoN, autoinhibitory N-terminal; CHD, chromodomain helicase DNA-binding; HSS, HAND-SANT-SLIDE; NegC, negative regulator of coupling.