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Review

Remodeler Catalyzed Nucleosome Repositioning: Influence of Structure and Stability

by
Aaron Morgan
,
Sarah LeGresley
and
Christopher Fischer
*
Department of Physics and Astronomy, University of Kansas, Lawrence, KS 66045, USA
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2021, 22(1), 76; https://doi.org/10.3390/ijms22010076
Submission received: 3 November 2020 / Revised: 4 December 2020 / Accepted: 16 December 2020 / Published: 23 December 2020
(This article belongs to the Special Issue Molecular Motors: From Single Molecules to Cooperative and Regulatory Mechanisms In Vivo)
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Abstract

:
The packaging of the eukaryotic genome into chromatin regulates the storage of genetic information, including the access of the cell’s DNA metabolism machinery. Indeed, since the processes of DNA replication, translation, and repair require access to the underlying DNA, several mechanisms, both active and passive, have evolved by which chromatin structure can be regulated and modified. One mechanism relies upon the function of chromatin remodeling enzymes which couple the free energy obtained from the binding and hydrolysis of ATP to the mechanical work of repositioning and rearranging nucleosomes. Here, we review recent work on the nucleosome mobilization activity of this essential family of molecular machines.

1. Introduction

The compaction of the eukaryotic genome into chromatin begins with the wrapping (i.e., bending) of the DNA around octamers of the H2A, H2B, H3, and H4 histone proteins to form nucleosomes [1,2,3,4]; two copies of each of these histones are found within each octamer. The DNA wrapped within each nucleosome, referred to as nucleosomal DNA, contacts the histone octamer at 14 different sites, spaced approximately 10 basepairs apart, each of which contains several different types of noncovalent interactions (e.g., van der Waals interactions, hydrogen bonds) between the DNA and the histones [1,3]. The histone octamer together with the ≈147 basepairs of nucleosomal DNA wrapped around it is referred to as the nucleosome core particle (NCP). A single base pair of the nucleosomal DNA is centered on the nucleosome dyad and defines the pseudo-two-fold symmetry axis of the NCP [5]. DNA locations are designated by superhelical locations (SHL) representing superhelical turns from the dyad (SHL0) and ranging from SHL−7 to SHL7 [5,6]. As shown in Figure 1,the next level of chromatin packing is the ordering of nucleosomes into a “beads on a string” structure in which individual nucleosomes are separated by short stretches of free DNA, flanking either side of the NCP, that link NCPs together [7]; this free DNA is most often referred to as linker DNA, but is sometimes called flanking DNA.
Since the packaging of DNA within nucleosomes requires that the DNA be wrapped around the histone octamer and that specific contacts be made between the DNA and the histones [1,2,3,4,8], it is not surprising that the thermodynamic stability of a nucleosome depends upon the sequence of the wrapped DNA [9,10,11,12,13]; however, DNA sequence has little affect on nucleosome structure [2]. For example, sequences of DNA that are more easily bent display a higher affinity for octamer binding [14] and nucleosomes reconstituted using such DNA sequences are also more stable [14]. The periodicity of particular dinucleotides in DNA sequences with high affinity for histone octamer binding further demonstrates the correlation between DNA sequence and nucleosome stability as the positions of these dinucleotides in the DNA increase the flexibility of the DNA, thereby facilitating the wrapping the DNA around the histone octamer [9,10,14]. To that point, it is worth noting that in several studies of nucleosome structure, nucleosomal DNA accessibility, and chromatin remodeling activity, the NCP substrates were reconstituted using a sequence of DNA, referred to as the Widom 601 sequence, that was designed to have high affinity for nucleosome binding [9].
The wrapping of nucleosomal DNA around the histone octamer restricts the ability of DNA binding proteins to access it [15,16,17]. Consequently, the wrapping of nucleosomal DNA must be dynamically controlled in order to regulate the accessibility of DNA repair, DNA replication, and gene expression machinery [18,19]. One mechanism of control involves the activity of molecular motors called chromatin remodelers, which reposition NCPs along DNA (i.e., move histone octamers relative to the DNA) using an ATP-dependent mechanism [20,21,22]. Chromatin remodelers have been shown to play a role in many biological processes, from regulation of gene expression to DNA damage response, and to catalyze many enzymatic reactions, including nucleosome assembly and disassembly [20,23,24,25,26,27]. Our focus here is a summary of recent studies of the nucleosome repositioning activity of chromatin remodelers only. Our aim in this manuscript is to highlight common elements of chromatin remodeler structures and repositioning mechanisms such that these lead to generalized conclusions about this activity. We also discuss how the perturbations of the network of interactions between the chromatin remodeler, the nucleosomal DNA, and the histone octamer modulate this activity.

2. Structure

Based upon their highly conserved ATPase domain, chromatin remodelers are classified as part of the large Snf2 family of proteins, which in turn is part of the helicase superfamily SF2 [23,28]. This ATPase consists of two tandem RecA-like folds (DExx and HELIC) that allow for translocation along the minor groove of DNA [29]. Chromatin remodelers are further categorized into four subfamilies—ISWI (imitation switch), SWI/SNF (switch/sucrose-non-fermenting), CHD (chromodomain-helicase-DNA binding), and INO80 (inositol requiring 80)—based on additional domains that confer specific functional properties [20,23,24]; a summary of these domains and their functions is presented in Table 1 and Figure 2. SWI/SNF chromatin remodelers share an HSA (helicase SANT) domain and a bromodomain, which is involved in binding actin and actin related proteins, and recognizing acetylated histones [25,30]; INO80 chromatin remodelers also contain an HSA domain, but lack bromodomains [20,25]. SWI/SNF and INO80 chromatin remodeling complexes have also been shown to contain actin and/or actin-related proteins (Arps) that may play a role in regulating the assembly of the complex and its interaction with chromatin [31,32]. ISWI chromain remodelers contain the HAND, SANT, and SLIDE domains which play roles in DNA and nucleosome binding [33,34]. As suggested by its name, CHD chromatin remodelers contain chromodomains that recognize methylated histones [20,35]. Furthermore, each of these subfamilies consist of multiple ATPases, several of which have been shown to possess distinct chromatin remodeling activity [20,36]. The number of individual chromatin-remodelers is further increased by counting the numerous large multiprotein complexes that share in common one of these ATPases [20]. Indeed, Saccharomyces cerevisiae alone contains two SWI/SNF ATPases, Swi2/Snf2 and Sth1, that serve as the molecular motors for the ySWI/SNF and RSC chromatin remodeling complexes, respectively [37]; two different ISWI ATPases, Isw1 and Isw2, which are found in four different chromatin remodeling complexes [38]; one CHD family chromatin remodeler, Chd1 [39]; and one INO80 family chromatin remodeler [40,41]. A similarly large array of chromatin remodelers has been found in other species [25]. Please note that we use the generic name chromatin remodeler in this report whether we are referring to a monomeric enzyme or a multiprotein complex; the reader should always be aware, however, that most chromatin remodelers function as complexes.
The regulation of the nucleosome binding and repositioning activity of chromatin remodelers has long been a topic of considerable interest [30,34,38,42,43,44,45,46,47]. The results of a recent cryo-EM study showed that the ATPase domain of the Chaetomium thermophilum ISWI chromatin remodeler interacted with the NCP at the SHL2 location, causing a bulge in the nucleosomal DNA there [48]. This bulge of DNA may be a common element of ISWI interactions with NCPs as it is also observed in the ADP bound state of the complex of Saccharomyces cerevisiae Isw1 with an NCP [49]; indeed, as discussed below, it is possible that the formation of this bulge of DNA is the first step in the process of DNA translocation that must accompany NCP repositioning. The results from both of these studies further suggest that rearrangements of the AutoN and NegC regulatory domains within the catalytic core of ISWI accompany the binding of the enzyme to the NCP [48,49]. These structural rearrangements may be necessary to facilitate the conformational changes within ISWI that are required for binding the NCP [48,49]. The similarity between the structures of apo-Isw1 interacting with an NCP and ADP-bound Isw1 interacting with an NCP is consistent with previous reports that nucleotide binding by Xenopus laevis ISWI did not modulate the affinity of that remodeler to bind an NCP [50], and that the structure of the histone octamer was unaffected by the binding of Chaetomium thermophilum ISWI [48]. When taken together, these data suggest that ISWI forms a DNA bulge by effectively competing with the histone for DNA biding rather than primarily through distortions of the histones themselves. Additional subunits within ISWI subfamily chromatin remodelers are also known to play a role in nucleosome binding. For example, the HAND, SANT, and SLIDE domains have been shown to bind DNA flanking the NCP [33,34]. Since mutations in the SLIDE domain affect that ATPase and nucleosome repositioning activities of Saccharomyces cerevisiae Isw2, a mechanistic role for this domain beyond that of nucleosome binding is likely [51].
The Saccharomyces cerevisiae Snf2 remodeler has also recently been shown to interact with the NCP at either the SHL2 or SHL6 location [52,53,54]. When bound at SHL2, Snf2 generates a bulge of DNA at that location [52,53], similar to what is observed with ISWI binding to SHL2 [48,49]; as with ISWI, it is the ATPase domain of Snf2 that contacts the DNA at this location. The formation of this DNA bulge is allosterically regulated through nucleotide binding by Snf2; the bulge is present when ADP-bound SNf2 or apo-SNF2 bind the nucleosome, but absent when ATP-bound Snf2 binds the nucleosome [53]. This bulge is associated with distortion throughout the nucleosomal DNA that is consistent with translocation of the DNA with respect to the histone octamer. Since the formation and resolution of the DNA bulge is associated with nucleotide binding by Snf2, structural changes in the Snf-nucleosome complex associated nucleotide binding by Snf2 could modulate a process of DNA translocation by the enzyme [53]. Furthermore, the presence of a secondary DNA binding surface in Snf2 allows for additional interactions between the remodeler and the DNA, which can help stabilize nucleosome binding and may play a role in DNA translocation [52]. Indeed, the importance of multiple DNA binding sites to processive DNA translocation by genetically related helicases has been well documented [55,56]. Although the physical significance of Snf2 binding at the SHL6 location has not yet been determined, it is worth noting that studies of NCP binding by other remodeling enzymes have indicated that multiple remodelers can interact with the same NCP [50,57,58,59].
A recent cryo-EM structure of the SWI/SNF chromatin remodeler RSC bound to a nucleosome also shows an interaction between the remodeler’s ATPase domain with the nucleosomal DNA at the SHL2 location with additional contacts between the remodeler and the nucleosomal DNA occurring at the SHL−6 and SHL−7 locations [60]. Furthermore, interactions between the ATPase domain and the SHL2 location have also been observed for chromatin remodelers from the CHD subfamily [61,62] as well as supplementary interactions at SHL−6, SHL−7, or SHL7 [61,62]. In contrast, the ATPase domain of INO80 has been shown to interact with the nucleosomal DNA at the SHL−7 location with the remodeler making additional nucleosomal contacts as SHL2, SHL−2, SHL3, or SHL−3 [54,63]. This frequently observed binding of chromatin remodeler’s ATPase domains to the SHL2 location may result from the fact that the nucleosomal DNA has high plasticity at that location [1]; the flexibility of the DNA at that location may make it easier for the remodeler to compete with the histones for DNA binding there. Similarly, the nearly universal occurrence of a second location for remodeler binding to the NCP, especially one close to the entry site of the NCP (e.g., at SHL6 or SHL7) may suggest a mechanism for DNA binding and translocation associated with nucleosome repositioning that is common to members of multiple subfamilies of chromatin remodelers. It is unfortunate, however, that uncertainty about the stoichiometry of chromatin remodeler binding to nucleosome substrates in several kinetic studies of NCP mobilization injects ambiguity in the interpretation of the roles of different structural elements of these enzymes in the mechanisms of nucleosome binding and repositioning, as well as the process of nucleosome repositioning itself.

3. Mechanisms of Nucleosome Repositioning

Nucleosome repositioning is an important part of the epigenetic regulation of gene expression. Chromatin remodelers modify nucleosome spacing through the sliding of NCPs relative to the DNA or by removing/exchanging histones from the NCP [64]. The former process relies upon the ability of the chromatin remodeler to translocate the nucleosomal DNA. Indeed, chromatin remodelers share the ATP-dependent DNA translocation activity of other members of the helicase superfamily SF2 [23,28,65,66,67,68,69,70]. Chromatin remodelers lack the helicase activity [71] of other SF2 enzymes, however, since their ATPase domain lacks the wedge domain necessary for DNA strand separation [72].
The isolated ATPase subunit of the ISWI chromatin remodeler family has been shown to be an ATP-dependent DNA translocase as well as a functional chromatin remodeler [66,70,73]. Single-stranded DNA translocation by the ISWI ATPase has a 3′ to 5′ directional bias and low processivity [66,70]. This low processivity may result from an allosteric regulation of DNA binding by nucleotide binding as the binding of ATP reduces the DNA binding affinity of ISWI [50]. In contrast, NCP binding by ISWI shows much higher affinity and is not allosterically regulated by nucleotide binding [50,73]. These results thus provide further evidence that the HAND, SANT, and SLIDE domains share additional histone recognition responsibilities beyond their reported role in DNA binding [28]. It is also interesting that, although ISWI is a poorly processive DNA translocase, it is nevertheless remarkably efficient, moving an average of 14 nucleotides per ATP molecule hydrolyzed [70]. It should be noted, however, that non-uniform motion may inflate the estimate of this distance [70]. Regardless, DNA translocation by ISWI is more efficient than the 1–4 nucleotides translocated per ATP molecule hydrolyzed that has been reported for genetically related helicases [74,75,76].
The coupling of ATP hydrolysis to the DNA translocation activity of a minimal construct of the essential SWI/SNF-family RSC chromatin remodeler, consisting of three of the fifteen subunits of the full length RSC [77,78], has also been characterized [69]. This minimal construct, denoted as RSCt, consists of the ARP7 and ARP9 subunits together with a truncated version of the Sth1 subunit, which contains the DNA-binding ATPase and translocation motor [78,79]. Similar to what has been observed with ISWI, RSCt displays a 3′ to 5′ directional bias for DNA translocation [65,67] and low translocation processivity [69]. In contrast to what was observed for ISWI, however, translocation by RSCt is not as energy efficient as DNA translocation by ISWI or genetically related helicases [74,75,76], requiring the hydrolysis of three ATP molecules for each nucleotide translocated [69]. RSCt was also shown to undergo an initiation process following its binding to DNA before becoming competent for DNA translocation and to be capable of exerting enough force during DNA translocation to disrupt a biotin–streptavidin linkage [69].
It is also interesting to note that the macroscopic rates of DNA translocation by ISWI and RSCt are similar to the macroscpoic rate of DNA translocation by the NS3h helicase from hepatitis C virus [75], but much slower than the macroscopic rates of DNA translocation by the UvrD [80], Rep [81], and T7 [74] helicases. This may suggest an underlying difference between helicase superfamilies with SFII helicases (NS3h, RSC, and ISWI) translocating along DNA much more slowly than SFI (UvrD and Rep) or DNAB-like (T7) helicases. Of course, while these results are interesting from the standpoint of making general comparisons, it is difficult to draw distinctive conclusions from them as these studies of these enzymes were performed under different conditions.
DNA translocation by remodelers does play a central role in many models of their nucleosome repositioning activity [28,49,53,65,73,82,83,84,85]. For example, the ATPase subunit of the Saccharomyces cerevisiae SWI/SNF and RSC chromatin remodelers are proposed to bind to a specific site within the NCP and subsequently engage in directional DNA translocation, pulling in DNA from one side of the NCP and pumping it out from the other side, to shift the histone octamer relative to the DNA [86,87]; this DNA translocation proceeds through the formation and propagation of DNA loops [65,67,87,88], twist defects in the DNA [89,90], or some combination of both (Figure 3). Thus, the SWI/SNF complex initiates nucleosome repositioning by competing with the histone octamer for DNA binding. The proposal that DNA loops are an intermediate in the nucleosome repositioning mechanism of SWI/SNF is further supported by observations that Saccharomyces cerevisiae RSC forms DNA loops during its translocation along free DNA [69,77,91] and with the formation of DNA loops in Snf-nucleosome complexes being allosterically regulated through nucleotide binding by Snf2 [53].
DNA translocation plays a similar role in models of nucleosome repositioning by ISWI. Based upon single-molecule experiments, a “power-stroke” model has been proposed for the DNA translocation associated with nucleosome repositioning by Saccharomyces cerevisiae Isw1 and Isw2 [85]. According to this model, the chromatin remodelers slide the DNA relative to the histone octamer through a coordinated mechanism controlling DNA entering or exiting the NCP [85]. The chromatin remodeler is bound to the linking DNA on either side of the NCP and initiates the repositioning reaction by translocating the nucleosomal DNA one basepair at a time toward one end of the NCP through an ATP-dependent mechanism, building up strain within the NCP between the DNA and the histones. After this strain becomes sufficiently strong, corresponding to seven basepairs of translocated nucleosomal DNA, a conformational change occurs between the linker-DNA-binding domain of the chromatin remodeler (possibly the SLIDE domain) and the ATPase domain, which pushes three basepairs of DNA into the NCP. This allows three basepairs of DNA to move outside the NCP from the other side of the NCP. This process then repeats in units of three basepairs translocated per translocation cycle. This model is consistent with the results of more recent ensemble experiments [92], theoretical analysis [93], and with the formation of DNA loops in Isw1-nucleosome complexes being allosterically regulated through nucleotide binding by Saccharomyces cerevisiae Isw1 [49]. In an alternative ‘ratchet’ model for nucleosome repositioning by ISWI, the ATPase domain of the ISWI complex is responsible for all mechanical processes associated with nucleosome repositioning [73]. Remodeling still originates from the seven base pairs of flanking DNA being pulled through the nucleosome by the ATPase domain which causes internal tensions that must be resolved through the breaking and reforming of connections between the histones and the nucleosomal DNA [73]. This model assumes that the HAND, SANT, and SLIDE domains are responsible for passive histone recognition and the removal of the NegC domain from the ATPase cleft [73,94,95]. In each of these two models for nucleosome repositioning by ISWI, multiple rounds of ATP hydrolysis are required to reposition the nucleosome. Although additional work is required to further discriminate between these two models, it is worth noting that the step-size observed for DNA translocation by isolated ATPase subunit of Xenopus laevis ISWI is similar to what is predicted for the initial step in the ‘ratchet’ model [70]. Lastly, the Saccharomyces cerevisiae INO80 chromatin remodeler is capable of moving an NCP from an end position to a more central position along DNA and may serve as a nucleosome spacing factor [96]. Although it has been proposed that NCP binding by INO80 depends upon the length of the DNA flanking the NCP [96], that assessment was made without a concomitant determination of the stoichiometry of INO80 binding to the NCP. Indeed, it is possible that the changes in the apparent K d of NCP binding by INO80 associated with increasing length of flanking DNA may be attributed to additional biding sites on the flanking DNA itself, as was observed for ISWI [50].
Although ATPase activity is required for remodeler function, several studies have shown that the movement of the histone octamer relative to the DNA is poorly coupled to ATP hydrolysis for Drosophila ACF [97], human Snf2H [98], and Xenopus laevis ISWI [92]. This poor coupling efficiency between ATPase activity and octamer movement could be a fundamental property of these motors (i.e., these motors are inherently inefficient at nucleosome repositioning) or it could result from significant ATP hydrolysis being associated with either futile repositioning or the initiation of repositioning. A large energetic cost for initiating the repositioning reaction seems unlikely as the bulges of DNA suggested to be the precursors of DNA translocation and nucleosome repositioning can be formed by chromatin remodelers binding to nucleosomes in the absence of ATP hydrolysis [48,49,53]. Since DNA translocation is fundamental to most models of nucleosome repositioning, DNA translocation has been proposed to be the energetically rate-limiting process during nucleosome repositioning [99]. However, since DNA translocation by chromatin remodelers is remarkably energy efficient [70], it seems unlikely that DNA translocation itself would be significantly less energy inefficient when coupled to nucleosome repositioning. However, since nucleosome repositioning requires the chromatin remodeler to break and reform contacts between the histones and the nucleosomal DNA in order for DNA translocation to occur, disrupting the interactions between the histones and the nucleosomal DNA does provide an energetic barrier to nucleosome repositioning. This barrier, if sufficiently large, could result in multiple rounds of unsuccessful attempts at nucleosome repositioning and the associated DNA translocation for each successful repositioning event [92,93]. This hypothesis could also explain the poor template commitment reported for human Snf2H [98] as well as the observation that Xenopus laevis ISWI repositions nucleosomes through a random walk mechanism [92]. Indeed, since most studies of chromatin remodeler function involve NCP substrates reconstituted using the Widom 601 DNA sequence [9], it is possible that experiments intended to assess the repositioning activity of chromatin remodelers, may instead report primarily on the affinity of histone:DNA interactions within the nucleosome rather than the activity of the remodeler. This proposition is further supported by the observation that the rate of nucleosome repositioning by Xenopus laevis ISWI depends upon the sequence of the nucleosomal DNA, with faster repositioning occurring with DNA sequences with lower affinity for histone binding [93]. Indeed, if the DNA translocation associated with nucleosome repositioning requires the chromatin remodeler to compete with the histones for binding the nucleosomal DNA [49,53,87], then it should be more difficult for chromatin remodelers to reposition nucleosomes reconstituted with DNA sequences with higher affinity for histone binding [93]. It is therefore not surprising that several studies have shown that the sequence of nucleosomal DNA influences the nucleosome repositioning activity of chromatin remodelers [92,100,101,102,103]. It is worth noting that the nucleosome repositioning activity of Saccharomyces cerevisiae INO80 has been reported to be independent of the sequence of nucleosomal DNA [104], but a lack of determination of the stoichiometry of INO80 binding to the NCP substrates used in these experiments creates some ambiguity in the interpretation of those results, especially for nucleosome substrates containing long lengths of DNA flanking the NCP [50,92]. While a dependence of nucleosome repositioning on the sequence of nucleosomal DNA may be helpful in providing an alternative tool for measuring DNA–histone interactions (i.e., an alternative probe of histone:DNA interaction free energy [10]), it clearly muddles what can be concluded about the intrinsic repositioning activity of the remodeler and how this activity is influenced and modulated [93].

4. Effects of Substrate Modification On NCP Binding and Mobilization

As discussed above, nucleosome repositioning requires the chromatin remodeler to compete with the histones for DNA binding so that DNA translocation can occur. As shown in Figure 4, nucleosome repositioning can thus be modulated by modifications within the network of interactions between the chromatin remodeler, the histones, and the DNA. Indeed, regulating the affinity of NCP binding and NCP mobilization (e.g., by affecting DNA translocation) through histone and/or DNA alterations is the basis of the proposal for kinetic proof-reading by chromatin remodelers [105,106,107]. For example, decreasing the affinity of NCP binding (i.e., increase the rate of dissociation from the NCP) due to a loss of contacts with the H4 tail or parts of the flanking DNA decreases the overall rate of NCP movement for human ACF1 [106]. Similarly, the strong affinity of histone binding by the Widom 601 sequence has been shown to modulate the NCP repositioning activity of Xenopus laevis ISWI [50,92]. In that case, the energetic barrier associated with disrupting histone:DNA contacts often prevented successive rounds of NCP movement before ISWI dissociation.
The ability of post-translational modification of histone proteins to influence interactions between chromatin remodelers and their nucleosome substrates provides an epigenetic mechanism of regulating the activity of these enzymes. Indeed, acetylation and methylation of the H3 and H4 histones is known to affect interactions between chromatin remodelers and NCPs [30,35,38,108,109,110] and thus serves as an regulator of transcription [111,112,113,114]. It is interesting to note that although the removal of the N-terminal tails of the H2A, H2B, and H3 histones do not affect the nucleosome repositioning activity of the ISWI subfamily chromatin remodelers CHRAC and NURF, removal of the N-terminal tail of the H4 histone blocks nucleosome repositioning by these remodelers [109,115,116]. Similarly, removal of the N-terminal tail of the H4 histone reduces the nucleosome repositioning activity of other ISWI and CHD subfamily chromatin remodelers [73,117,118,119]. Since the N-terminal tail of the H4 histone is at the SHL2 location, which, as discussed above, is where the ATPase domain of many chromatin remodelers bind the NCP, it is not surprising that it is required for the binding of Saccharomyces cerevisiae ISW2 to SHL2 [117]. In contrast, deletion of the N-terminal tail of the H4 histone was shown to reduce the nucleosome repositioning activity of the SWI/SNF subfamily chromatin remodeler RSC and the CHD subfamily chromatin remodeler Chd1, without reducing the affinity of NCP binding by those enzymes [118]. While these latter results suggest a possible mechanistic role for this tail in addition to its role in regulating NCP binding affinity, it is important to note that binding affinity was assessed through the Michaelis–Menten parameter K M [118] rather than equilibrium measurements of NCP binding and the allosteric regulation of it by nucleotide binding. Lastly, the sequence of the auto-inhibitory region of ISWI, denoted as AutoN, has high similarity to the sequence of the N-terminal tail of histone H4 [94]. When ISWI binds to an NCP, the ATPase domain of ISWI interacts with the N-terminal tail of histone H4, rather than AutoN [48].
Modifications of the N-terminal tail of histone H3 have also been shown to affect NCP binding and mobilization. The SWI/SNF and ISWI family chromatin remodelers were shown to bind H3K9AcK14Ac-containing di-nucleosomes with significantly higher affinity than unmodified di-nucleosomes [120]. Since these complexes consist of multiple subunits, each of which with a separate affinity for binding modified and unmodified di-nucleosomes, it is important to recognize that the binding behavior of a given remodeler complex is a convolution or superposition of the binding behaviors of its subunits. Indeed, the PHF10 subunit of SWI/SNF appears to preferentially interact with H3K9AcK14Ac, displaying one of the highest affinities for this modification of all SWI/SNF family subunits, while seeming to be repelled by H3K4me3 [120]. In contrast, the SMARCA2 and SMARCA4 subunits of SWI/SNF engage in high affinity interactions with H3K4me3 modified di-nucleosomes [120]. The ISWI catalytic subunit SMARCA5 and accessory subunits BPTF, C17orf49, BAZIA, and BAZIB display relatively high affinity for both modified and unmodified di-nucleosomes, with SMARCA5 preferentially binding H3K9AcK14Ac-modified over H3K4me3-modified or unmodified di-nucleosomes [120]. It is worth noting, however, that although these accessory subunits all show high affinity for binding these modified substrates, they each exhibit distinct binding interactions with them [120]. Similarly, the binding behaviors of complexes such as NuRF, ACF, and WICH—each containing a different subset of SMARCA5 and the previously mentioned ISWI family accessory subunits—likely represent convolutions of the binding behaviors of their respective subunits [120]. Clearly, additional characterizations of the binding contributions of the constituent subunits of chromatin remodeling complexes can provide further insight into not only how these complexes are regulated by post-translational modifications, but also into their nucleosome binding and repositioning activities themselves. Such studies could also identify common elements of behavior and regulation. For example, is it the case that a complex containing SMARCA2/4 will always see an increased affinity for H3K4me3, while a complex containing PHF10 will always see a reduced affinity? If so, that what evolutionary pressures led to the incorporation of different subunits into different complexes?
Amino acids within the H2A and H2B histones create a negative charged region on the surface of the NCP [1]. This acidic patch has been shown to be a target for several nucleosome-interacting proteins and to play a role in the formation of the higher-order chromatin structures shown in Figure 1 [121,122,123]. Indeed, several chromatin remodelers have been shown to possess a region of positive charge, commonly referred to as a basic motif, that interacts directly with the NCP acidic path during NCP binding [8,124]. One example of this is the previous mentioned AutoN and NegC domains of the ISWI subfamily chromatin remodeler SNF2h, which have been shown to interact directly with the acidic patch of the NCP [125]. Mutations in either the AutoN or NegC domains reduce the requirements of the negative charges in the acidic patch of the NCP for optimal nucleosome repositioning [125]. Decreasing the negative charge within the acidic patch also decreases the rate of nucleosome repositioning by the Saccharomyces cerevisiae INO80 chromatin remodeler [125]. It is also worth noting that the chromatin substrates of the INO80 subfamily include the histone H2A variants H2AZ and H2AX, and the interaction between INO80 and phosphorylated H2AX within the nucleosome is mediated by INO80’s Nhp10 and Arp4 subunits [126]; the histone variants H2AZ and H2AX are implicated in numerous cellular processes through their roles in regulating transcription and DNA repair [127,128,129].
Different chromatin remodeler complexes, including complexes possessing differing ATPase domains and accessory proteins, establish unique nucleosome positioning patterns [100,130]. For example, the final NCP positions resulting from nucleosome repositioning by the human Snf2H remodeling complex depended upon whether the Tip5 domain was present in the complex [100,101]. Similarly, studies employing electrophoretic mobility assays to compare the repositioning activity of a range of chromatin remodelers—Brg1, Chd1, ISWI, Snf2H, Mi-2, ACF, INO80, and NURF—showed that each has its own preference for repositioning nucleosomes into a particular set of positions (i.e., nucleosome spacing). Because it appears that intermediate positions remain mostly identical to initial nucleosome positions it has been suggested that positioning patterns are the result of unique interpretations of DNA sequence/structure information, resulting in unique distributions of affinity for different nucleosome positions by chromatin remodelers with differing ATPase motor proteins and non-catalytic accessory proteins [100]. For example, Xenopus laevis ISWI was shown to move NCPs between positions corresponding to minimum energy states in the interactions between the histones and the DNA [92,93]. However, the panoply of interactions between the histones, the nucleosomal DNA, and the chromatin remodeler (Figure 4) has yet to be fully and independently characterized for any system. In the absence of such a characterization, it is not possible to conclude that the pattern of nucleosome positioning a particular chromatin remodeler displays is wholly a result of the effects of nucleosome position on the affinity of nucleosome biding by the remodeler and not—at least in part—a result of the remodeler’s unique capability for disrupting the binding of particular sets of nucleosomal DNA sequences to the histone. Indeed, the apparent poor coupling of NCP repositioning to ATP binding and hydrolysis for Drosophila ACF [97], human Snf2H [98], and Xenopus laevis ISWI [92] suggests that nucleosome repositioning patterns are likely influenced by more than a remodeler’s affinity for a set of substrates, consistent with kinetic proof-reading models [105,106,107]. Furthermore, the genome-wide distributions of Drosophilia NURD, (P)BAP, INO80, and ISWI chromatin remodelers indicate that each of these chromatin remodelers has a specific set of repositioning targets and generates distinct nucleosome distributions [131], likely resulting from variations in affinity of genomic DNA for binding the histone octamer and variations in the location concentration of the chromatin remodelers and their affinity for NCP binding, including its regulation by post-translational modifications.
The fact that the sequence of nucleosomal DNA influences the nucleosome repositioning activity of chromatin remodelers [92,93,100,101,102,103] provides another mechanism of regulating the activity of these enzymes. Of particular interest is the role of chromatin remodelers in DNA damage detection and repair. For example, the NuRD complex and, in particular, its subunit CHD4 have been shown to play a role in the repair of double-stranded DNA breaks [132,133]. Similarly, the INO80 chromatin remodeler is proposed to play a role in in homologous recombination and DNA replication by preferentially binding to four-way junctions or three-way junctions and evicting nucleosomes near double stranded breaks [126,134]. While histone modifications may be responsible for some of the regulation of chromatin remodeling activity as part of DNA damage detection and repair [135], it has also been suggested recently that DNA damage induced changes in the free-energies of interactions among the DNA, the histones, and the chromatin remodeler may favor chromatin remodelers repositioning nucleosomes to locations where the DNA damage can be more easily detected and repaired [93,136]. Thus, the thermodynamics associated with the packaging of DNA into nucleosomes might allow DNA damage to facilitate its own detection, which could provide eukaryotes with a significant evolutionary advantage.

5. Outlook

The nucleosome repositioning activity of chromatin remodelers is an emergent property of variations within the network of interactions among the remodeler, the nucleosomal DNA, and the histones, with the interactions of the chromatin remodelers further allosterically regulated by ATP binding and hydrolysis. Post-translational modifications of the histones and/or the chromatin remodelers include specific targeting of subunits or accessory proteins within the chromatin remodeler, and variations in DNA sequence provide a further mechanism of control and regulation. In light of this, future studies of the nucleosome repositioning activity of chromatin remodelers would benefit from a systematic and holistic characterization of the interactions in this network. This should include coordinated studies of nucleosome binding and repositioning so that the fraction and identification of bound species in the repositioning reaction is known [50,92]. These experiments should also be conducted using a range of sequences for the nucleosomal DNA and a variety of histone post-translational modifications, coupled with independent determinations of the stability of each nucleosome substrate, so that changes in the rate of nucleosome repositioning can be correlated with changes in the energetics of the remodeler-NCP interaction or nucleosome stability [93]. In addition to being the most effective pathway to characterizing correctly the NCP binding and mobilization activity of chromatin remodelers, such an approach would also be applicable for future studies of how chromatin remodelers interact with other elements of the cell’s DNA transcription, repair, and replication machinery to regulate these essential biological functions [105].

Author Contributions

All authors contributed equally to the writing of this manuscript. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Luger, K.; Mader, A.W.; Richmond, R.K.; Sargent, D.F.; Richmond, T.J. Crystal structure of the nucleosome core particle at 2.8 angstrom resolution. Nature 1997, 389, 251. [Google Scholar] [CrossRef] [PubMed]
  2. Davey, C.A.; Sargent, D.F.; Luger, K.; Maeder, A.W.; Richmond, T.J. Solvent mediated interactions in the structure of the nucleosome core particle at 1.9 Å resolution. J. Mol. Biol. 2002, 319, 1097–1113. [Google Scholar] [CrossRef]
  3. Richmond, T.J.; Davey, C.A. The structure of DNA in the nucleosome core. Nature 2003, 423, 145. [Google Scholar] [CrossRef] [PubMed]
  4. Frouws, T.D.; Duda, S.C.; Richmond, T.J. X-ray structure of the MMTV-A nucleosome core. Proc. Natl. Acad. Sci. USA 2016, 113, 1214–1219. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  5. Flaus, A.; Luger, K.; Tan, S.; Richmond, T.J. Mapping nucleosome position at single base-pair resolution by using site-directed hydroxyl radicals. Proc. Natl. Acad. Sci. USA 1996, 93, 1370–1375. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  6. McGinty, R.K.; Tan, S. Nucleosome structure and function. Chem. Rev. 2015, 115, 2255–2273. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  7. Szerlong, H.J.; Hansen, J.C. Nucleosome distribution and linker DNA: connecting nuclear function to dynamic chromatin structure. Biochem. Cell Biol. 2011, 89, 24–34. [Google Scholar] [CrossRef] [Green Version]
  8. Dann, G.P.; Liszczak, G.P.; Bagert, J.D.; Müller, M.M.; Nguyen, U.T.; Wojcik, F.; Brown, Z.Z.; Bos, J.; Panchenko, T.; Pihl, R.; et al. ISWI chromatin remodellers sense nucleosome modifications to determine substrate preference. Nature 2017, 548, 607–611. [Google Scholar] [CrossRef] [Green Version]
  9. Lowary, P.; Widom, J. New DNA sequence rules for high affinity binding to histone octamer and sequence-directed nucleosome positioning. J. Mol. Biol. 1998, 276, 19–42. [Google Scholar] [CrossRef]
  10. Thåström, A.; Lowary, P.; Widom, J. Measurement of histone–DNA interaction free energy in nucleosomes. Methods 2004, 33, 33–44. [Google Scholar] [CrossRef]
  11. Battistini, F.; Hunter, C.A.; Moore, I.K.; Widom, J. Structure-based identification of new high-affinity nucleosome binding sequences. J. Mol. Biol. 2012, 420, 8–16. [Google Scholar] [CrossRef] [PubMed]
  12. Ngo, T.T.; Yoo, J.; Dai, Q.; Zhang, Q.; He, C.; Aksimentiev, A.; Ha, T. Effects of cytosine modifications on DNA flexibility and nucleosome mechanical stability. Nat. Commun. 2016, 7, 1–9. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  13. Tóth, K.; Böhm, V.; Sellmann, C.; Danner, M.; Hanne, J.; Berg, M.; Barz, I.; Gansen, A.; Langowski, J. Histone-and DNA sequence-dependent stability of nucleosomes studied by single-pair FRET. Cytom. Part A 2013, 83, 839–846. [Google Scholar] [CrossRef] [PubMed]
  14. Widom, J. Role of DNA sequence in nucleosome stability and dynamics. Q. Rev. Biophys. 2001, 34, 269–324. [Google Scholar] [CrossRef] [PubMed]
  15. Polach, K.; Widom, J. Mechanism of protein access to specific DNA sequences in chromatin: A dynamic equilibrium model for gene regulation. J. Mol. Biol. 1995, 254, 130–149. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  16. Anderson, J.; Widom, J. Sequence and position-dependence of the equilibrium accessibility of nucleosomal DNA target sites. J. Mol. Biol. 2000, 296, 979–987. [Google Scholar] [CrossRef] [PubMed]
  17. Li, G.; Widom, J. Nucleosomes facilitate their own invasion. Nat. Struct. Mol. Biol. 2004, 11, 763–769. [Google Scholar] [CrossRef] [PubMed]
  18. Azmi, I.F.; Watanabe, S.; Maloney, M.F.; Kang, S.; Belsky, J.A.; MacAlpine, D.M.; Peterson, C.L.; Bell, S.P. Nucleosomes influence multiple steps during replication initiation. eLife 2017, 6, e22512. [Google Scholar] [CrossRef] [Green Version]
  19. Kadonaga, J.T. Eukaryotic transcription: an interlaced network of transcription factors and chromatin-modifying machines. Cell 1998, 92, 307–313. [Google Scholar] [CrossRef] [Green Version]
  20. Clapier, C.R.; Cairns, B.R. The biology of chromatin remodeling complexes. Annu. Rev. Biochem. 2009, 78, 273–304. [Google Scholar] [CrossRef]
  21. Bowman, G.D. Mechanisms of ATP-dependent nucleosome sliding. Curr. Opin. Struct. Biol. 2010, 20, 73–81. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  22. Clapier, C.R.; Iwasa, J.; Cairns, B.R.; Peterson, C.L. Mechanisms of action and regulation of ATP-dependent chromatin-remodelling complexes. Nat. Rev. Mol. Cell Biol. 2017, 18, 407–422. [Google Scholar] [CrossRef]
  23. Eisen, J.A.; Sweder, K.S.; Hanawalt, P.C. Evolution of the SNF2 family of proteins: subfamilies with distinct sequences and functions. Nucleic Acids Res. 1995, 23, 2715–2723. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  24. Lusser, A.; Kadonaga, J.T. Chromatin remodeling by ATP-dependent molecular machines. Bioessays 2003, 25, 1192–1200. [Google Scholar] [CrossRef] [PubMed]
  25. Tyagi, M.; Imam, N.; Verma, K.; Patel, A.K. Chromatin remodelers: We are the drivers! Nucleus 2016, 7, 388–404. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  26. Markert, J.; Luger, K. Nucleosomes Meet Their Remodeler Match. Trends Biochem. Sci. 2020. [Google Scholar] [CrossRef]
  27. Peng, A.Y.T.; Kolhe, J.A.; Behrens, L.D.; Freeman, B.C. Genome organization: Tag it, move it, place it. Current Opinion in Cell Biology 2020, 68, 90–97. [Google Scholar] [CrossRef]
  28. Mueller-Planitz, F.; Klinker, H.; Becker, P.B. Nucleosome sliding mechanisms: new twists in a looped history. Nat. Struct. Mol. Biol. 2013, 20, 1026–1032. [Google Scholar] [CrossRef]
  29. Singleton, M.R.; Dillingham, M.S.; Wigley, D.B. Structure and mechanism of helicases and nucleic acid translocases. Annu. Rev. Biochem. 2007, 76, 23–50. [Google Scholar] [CrossRef]
  30. Marmorstein, R.; Berger, S.L. Structure and function of bromodomains in chromatin-regulating complexes. Gene 2001, 272, 1–9. [Google Scholar] [CrossRef]
  31. Olave, I.A.; Reck-Peterson, S.L.; Crabtree, G.R. Nuclear actin and actin-related proteins in chromatin remodeling. Annu. Rev. Biochem. 2002, 71, 755–781. [Google Scholar] [CrossRef] [PubMed]
  32. Szerlong, H.; Saha, A.; Cairns, B.R. The nuclear actin-related proteins Arp7 and Arp9: a dimeric module that cooperates with architectural proteins for chromatin remodeling. EMBO J. 2003, 22, 3175–3187. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  33. Zofall, M.; Persinger, J.; Bartholomew, B. Functional role of extranucleosomal DNA and the entry site of the nucleosome in chromatin remodeling by ISW2. Mol. Cell. Biol. 2004, 24, 10047–10057. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  34. Petty, E.; Pillus, L. Balancing chromatin remodeling and histone modifications in transcription. Trends Genet. 2013, 29, 621–629. [Google Scholar] [CrossRef] [Green Version]
  35. Wang, S.S.; Zhou, B.O.; Zhou, J.Q. Histone H3 lysine 4 hypermethylation prevents aberrant nucleosome remodeling at the PHO5 promoter. Mol. Cell. Biol. 2011, 31, 3171–3181. [Google Scholar] [CrossRef] [Green Version]
  36. Becker, P.B.; Hörz, W. ATP-dependent nucleosome remodeling. Annu. Rev. Biochem. 2002, 71, 247–273. [Google Scholar] [CrossRef]
  37. Cairns, B.R.; Lorch, Y.; Li, Y.; Zhang, M.; Lacomis, L.; Erdjument-Bromage, H.; Tempst, P.; Du, J.; Laurent, B.; Kornberg, R.D. RSC, an essential, abundant chromatin-remodeling complex. Cell 1996, 87, 1249–1260. [Google Scholar] [CrossRef] [Green Version]
  38. Toto, M.; D’Angelo, G.; Corona, D.F. Regulation of ISWI chromatin remodelling activity. Chromosoma 2014, 123, 91–102. [Google Scholar] [CrossRef] [Green Version]
  39. Tran, H.G.; Steger, D.J.; Iyer, V.R.; Johnson, A.D. The chromo domain protein Chd1p from budding yeast is an ATP-dependent chromatin-modifying factor. EMBO J. 2000, 19, 2323–2331. [Google Scholar] [CrossRef] [Green Version]
  40. Ebbert, R.; Birkmann, A.; Schüller, H.J. The product of the SNF2/SWI2 paralogue INO80 of Saccharomyces cerevisiae required for efficient expression of various yeast structural genes is part of a high-molecular-weight protein complex. Mol. Microbiol. 1999, 32, 741–751. [Google Scholar] [CrossRef]
  41. Klopf, E.; Paskova, L.; Solé, C.; Mas, G.; Petryshyn, A.; Posas, F.; Wintersberger, U.; Ammerer, G.; Schüller, C. Cooperation between the INO80 complex and histone chaperones determines adaptation of stress gene transcription in the yeast Saccharomyces cerevisiae. Mol. Cell. Biol. 2009, 29, 4994–5007. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  42. Varga-Weisz, P.D.; Wilm, M.; Bonte, E.; Dumas, K.; Mann, M.; Becker, P.B. Chromatin-remodelling factor CHRAC contains the ATPases ISWI and topoisomerase II. Nature 1997, 388, 598–602. [Google Scholar] [CrossRef]
  43. Vary, J.C., Jr.; Gangaraju, V.K.; Qin, J.; Landel, C.C.; Kooperberg, C.; Bartholomew, B.; Tsukiyama, T. Yeast Isw1p forms two separable complexes in vivo. Mol. Cell. Biol. 2003, 23, 80–91. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  44. Jónsson, Z.O.; Jha, S.; Wohlschlegel, J.A.; Dutta, A. Rvb1p/Rvb2p recruit Arp5p and assemble a functional Ino80 chromatin remodeling complex. Mol. Cell 2004, 16, 465–477. [Google Scholar] [CrossRef] [PubMed]
  45. Bouazoune, K.; Brehm, A. ATP-dependent chromatin remodeling complexes in Drosophila. Chromosome Res. 2006, 14, 433–449. [Google Scholar] [CrossRef]
  46. Hall, J.A.; Georgel, P.T. CHD proteins: A diverse family with strong ties. Biochem. Cell Biol. 2007, 85, 463–476. [Google Scholar] [CrossRef]
  47. Marfella, C.G.; Imbalzano, A.N. The Chd family of chromatin remodelers. Mutat. Res. Mol. Mech. Mutagen. 2007, 618, 30–40. [Google Scholar] [CrossRef] [Green Version]
  48. Chittori, S.; Hong, J.; Bai, Y.; Subramaniam, S. Structure of the primed state of the ATPase domain of chromatin remodeling factor ISWI bound to the nucleosome. Nucleic Acids Res. 2019, 47, 9400–9409. [Google Scholar] [CrossRef]
  49. Yan, L.; Wu, H.; Li, X.; Gao, N.; Chen, Z. Structures of the ISWI–nucleosome complex reveal a conserved mechanism of chromatin remodeling. Nat. Struct. Mol. Biol. 2019, 26, 258–266. [Google Scholar] [CrossRef]
  50. Al-Ani, G.; Briggs, K.; Malik, S.S.; Conner, M.; Azuma, Y.; Fischer, C.J. Quantitative determination of binding of ISWI to nucleosomes and DNA shows allosteric regulation of DNA binding by nucleotides. Biochemistry 2014, 53, 4334–4345. [Google Scholar] [CrossRef]
  51. Hota, S.K.; Bhardwaj, S.K.; Deindl, S.; Lin, Y.c.; Zhuang, X.; Bartholomew, B. Nucleosome mobilization by ISW2 requires the concerted action of the ATPase and SLIDE domains. Nat. Struct. Mol. Biol. 2013, 20, 222. [Google Scholar] [CrossRef]
  52. Liu, X.; Li, M.; Xia, X.; Li, X.; Chen, Z. Mechanism of chromatin remodelling revealed by the Snf2-nucleosome structure. Nature 2017, 544, 440–445. [Google Scholar] [CrossRef]
  53. Li, M.; Xia, X.; Tian, Y.; Jia, Q.; Liu, X.; Lu, Y.; Li, M.; Li, X.; Chen, Z. Mechanism of DNA translocation underlying chromatin remodelling by Snf2. Nature 2019, 567, 409–413. [Google Scholar] [CrossRef]
  54. Han, Y.; Reyes, A.A.; Malik, S.; He, Y. Cryo-EM structure of SWI/SNF complex bound to a nucleosome. Nature 2020, 579, 452–455. [Google Scholar] [CrossRef]
  55. Lohman, T.M.; Hsieh, J.; Maluf, N.K.; Cheng, W.; Lucius, A.L.; Fischer, C.J.; Brendza, K.M.; Korolev, S.; Waksman, G. DNA helicases, motors that move along nucleic acids: lessons from the SF1 helicase superfamily. In The Enzymes; Elsevier: Amsterdam, The Netherlands, 2003; Volume 23, pp. 303–311. [Google Scholar]
  56. Fischer, C.J.; Wooten, L.; Tomko, E.J.; Lohman, T.M. Kinetics of motor protein translocation on single-stranded DNA. In Helicases; Springer: Berlin/Heidelberg, Germany, 2009; pp. 45–56. [Google Scholar]
  57. Blosser, T.R.; Yang, J.G.; Stone, M.D.; Narlikar, G.J.; Zhuang, X. Dynamics of nucleosome remodelling by individual ACF complexes. Nature 2009, 462, 1022. [Google Scholar] [CrossRef] [Green Version]
  58. Racki, L.R.; Yang, J.G.; Naber, N.; Partensky, P.D.; Acevedo, A.; Purcell, T.J.; Cooke, R.; Cheng, Y.; Narlikar, G.J. The chromatin remodeler ACF acts as a dimeric motor to space nucleosomes. Nature 2009, 462, 1016. [Google Scholar] [CrossRef] [Green Version]
  59. Brehm, A.; Längst, G.; Kehle, J.; Clapier, C.R.; Imhof, A.; Eberharter, A.; Müller, J.; Becker, P.B. dMi-2 and ISWI chromatin remodelling factors have distinct nucleosome binding and mobilization properties. EMBO J. 2000, 19, 4332–4341. [Google Scholar] [CrossRef] [Green Version]
  60. Wagner, F.R.; Dienemann, C.; Wang, H.; Stützer, A.; Tegunov, D.; Urlaub, H.; Cramer, P. Structure of SWI/SNF chromatin remodeller RSC bound to a nucleosome. Nature 2020, 579, 448–451. [Google Scholar] [CrossRef]
  61. Farnung, L.; Vos, S.M.; Wigge, C.; Cramer, P. Nucleosome–Chd1 structure and implications for chromatin remodelling. Nature 2017, 550, 539–542. [Google Scholar] [CrossRef]
  62. Armache, J.P.; Gamarra, N.; Johnson, S.L.; Leonard, J.D.; Wu, S.; Narlikar, G.J.; Cheng, Y. Cryo-EM structures of remodeler-nucleosome intermediates suggest allosteric control through the nucleosome. Elife 2019, 8, e46057. [Google Scholar] [CrossRef]
  63. Patel, A.B.; Moore, C.M.; Greber, B.J.; Luo, J.; Zukin, S.A.; Ranish, J.; Nogales, E. Architecture of the chromatin remodeler RSC and insights into its nucleosome engagement. Elife 2019, 8, e54449. [Google Scholar] [CrossRef]
  64. Narlikar, G.J.; Sundaramoorthy, R.; Owen-Hughes, T. Mechanisms and functions of ATP-dependent chromatin-remodeling enzymes. Cell 2013, 154, 490–503. [Google Scholar] [CrossRef] [Green Version]
  65. Saha, A.; Wittmeyer, J.; Cairns, B.R. Chromatin remodeling by RSC involves ATP-dependent DNA translocation. Genes Dev. 2002, 16, 2120–2134. [Google Scholar] [CrossRef] [Green Version]
  66. Whitehouse, I.; Stockdale, C.; Flaus, A.; Szczelkun, M.D.; Owen-Hughes, T. Evidence for DNA translocation by the ISWI chromatin-remodeling enzyme. Mol. Cell. Biol. 2003, 23, 1935–1945. [Google Scholar] [CrossRef] [Green Version]
  67. Zhang, Y.; Smith, C.L.; Saha, A.; Grill, S.W.; Mihardja, S.; Smith, S.B.; Cairns, B.R.; Peterson, C.L.; Bustamante, C. DNA translocation and loop formation mechanism of chromatin remodeling by SWI/SNF and RSC. Mol. Cell 2006, 24, 559–568. [Google Scholar] [CrossRef]
  68. Lia, G.; Indrieri, M.; Owen-Hughes, T.; Finzi, L.; Podesta, A.; Milani, P.; Dunlap, D. ATP-dependent looping of DNA by ISWI. J. Biophotonics 2008, 1, 280–286. [Google Scholar] [CrossRef] [Green Version]
  69. Eastlund, A.; Malik, S.S.; Fischer, C.J. Kinetic mechanism of DNA translocation by the RSC molecular motor. Arch. Biochem. Biophys. 2013, 532, 73–83. [Google Scholar] [CrossRef] [Green Version]
  70. Eastlund, A.; Al-Ani, G.; Fischer, C.J. Low processivity for DNA translocation by the ISWI molecular motor. Biochim. Biophys. Acta-(Bba)-Proteins Proteom. 2015, 1854, 1487–1493. [Google Scholar] [CrossRef]
  71. Côté, J.; Peterson, C.L.; Workman, J.L. Perturbation of nucleosome core structure by the SWI/SNF complex persists after its detachment, enhancing subsequent transcription factor binding. Proc. Natl. Acad. Sci. USA 1998, 95, 4947–4952. [Google Scholar] [CrossRef] [Green Version]
  72. Dürr, H.; Körner, C.; Müller, M.; Hickmann, V.; Hopfner, K.P. X-ray structures of the Sulfolobus solfataricus SWI2/SNF2 ATPase core and its complex with DNA. Cell 2005, 121, 363–373. [Google Scholar] [CrossRef] [Green Version]
  73. Mueller-Planitz, F.; Klinker, H.; Ludwigsen, J.; Becker, P.B. The ATPase domain of ISWI is an autonomous nucleosome remodeling machine. Nat. Struct. Mol. Biol. 2013, 20, 82–89. [Google Scholar] [CrossRef]
  74. Kim, D.E.; Narayan, M.; Patel, S.S. T7 DNA helicase: a molecular motor that processively and unidirectionally translocates along single-stranded DNA. J. Mol. Biol. 2002, 321, 807–819. [Google Scholar] [CrossRef]
  75. Khaki, A.R.; Field, C.; Malik, S.; Niedziela-Majka, A.; Leavitt, S.A.; Wang, R.; Hung, M.; Sakowicz, R.; Brendza, K.M.; Fischer, C.J. The macroscopic rate of nucleic acid translocation by hepatitis C virus helicase NS3h is dependent on both sugar and base moieties. J. Mol. Biol. 2010, 400, 354–378. [Google Scholar] [CrossRef] [Green Version]
  76. Tomko, E.J.; Fischer, C.J.; Lohman, T.M. Single-stranded DNA translocation of E. coli UvrD monomer is tightly coupled to ATP hydrolysis. J. Mol. Biol. 2012, 418, 32–46. [Google Scholar] [CrossRef] [Green Version]
  77. Sirinakis, G.; Clapier, C.R.; Gao, Y.; Viswanathan, R.; Cairns, B.R.; Zhang, Y. The RSC chromatin remodelling ATPase translocates DNA with high force and small step size. EMBO J. 2011, 30, 2364–2372. [Google Scholar] [CrossRef]
  78. Malik, S.S.; Rich, E.; Viswanathan, R.; Cairns, B.R.; Fischer, C.J. Allosteric interactions of DNA and nucleotides with S. cerevisiae RSC. Biochemistry 2011, 50, 7881–7890. [Google Scholar] [CrossRef] [Green Version]
  79. Cairns, B.R.; Erdjument-Bromage, H.; Tempst, P.; Winston, F.; Kornberg, R.D. Two actin-related proteins are shared functional components of the chromatin-remodeling complexes RSC and SWI/SNF. Mol. Cell 1998, 2, 639–651. [Google Scholar] [CrossRef]
  80. Fischer, C.J.; Maluf, N.K.; Lohman, T.M. Mechanism of ATP-dependent translocation of E. coli UvrD monomers along single-stranded DNA. J. Mol. Biol. 2004, 344, 1287–1309. [Google Scholar] [CrossRef]
  81. Brendza, K.M.; Cheng, W.; Fischer, C.J.; Chesnik, M.A.; Niedziela-Majka, A.; Lohman, T.M. Autoinhibition of Escherichia coli Rep monomer helicase activity by its 2B subdomain. Proc. Natl. Acad. Sci. USA 2005, 102, 10076–10081. [Google Scholar] [CrossRef] [Green Version]
  82. Eberharter, A.; Vetter, I.; Ferreira, R.; Becker, P.B. ACF1 improves the effectiveness of nucleosome mobilization by ISWI through PHD–histone contacts. EMBO J. 2004, 23, 4029–4039. [Google Scholar] [CrossRef] [Green Version]
  83. Strohner, R.; Wachsmuth, M.; Dachauer, K.; Mazurkiewicz, J.; Hochstatter, J.; Rippe, K.; Längst, G. A ‘loop recapture’ mechanism for ACF-dependent nucleosome remodeling. Nat. Struct. Mol. Biol. 2005, 12, 683. [Google Scholar] [CrossRef]
  84. Zofall, M.; Persinger, J.; Kassabov, S.R.; Bartholomew, B. Chromatin remodeling by ISW2 and SWI/SNF requires DNA translocation inside the nucleosome. Nat. Struct. Mol. Biol. 2006, 13, 339–346. [Google Scholar] [CrossRef]
  85. Deindl, S.; Hwang, W.L.; Hota, S.K.; Blosser, T.R.; Prasad, P.; Bartholomew, B.; Zhuang, X. ISWI remodelers slide nucleosomes with coordinated multi-base-pair entry steps and single-base-pair exit steps. Cell 2013, 152, 442–452. [Google Scholar] [CrossRef] [Green Version]
  86. Dechassa, M.L.; Zhang, B.; Horowitz-Scherer, R.; Persinger, J.; Woodcock, C.L.; Peterson, C.L.; Bartholomew, B. Architecture of the SWI/SNF-nucleosome complex. Mol. Cell. Biol. 2008, 28, 6010–6021. [Google Scholar] [CrossRef] [Green Version]
  87. Lorch, Y.; Maier-Davis, B.; Kornberg, R.D. Mechanism of chromatin remodeling. Proc. Natl. Acad. Sci. USA 2010, 107, 3458–3462. [Google Scholar] [CrossRef] [Green Version]
  88. Saha, A.; Wittmeyer, J.; Cairns, B.R. Chromatin remodeling through directional DNA translocation from an internal nucleosomal site. Nat. Struct. Mol. Biol. 2005, 12, 747–755. [Google Scholar] [CrossRef]
  89. Kulić, I.; Schiessel, H. Chromatin dynamics: nucleosomes go mobile through twist defects. Phys. Rev. Lett. 2003, 91, 148103. [Google Scholar] [CrossRef] [Green Version]
  90. Brandani, G.B.; Takada, S. Chromatin remodelers couple inchworm motion with twist-defect formation to slide nucleosomal DNA. PLoS Comput. Biol. 2018, 14, e1006512. [Google Scholar] [CrossRef] [Green Version]
  91. Fischer, C.J.; Saha, A.; Cairns, B.R. Kinetic model for the ATP-dependent translocation of Saccharomyces cerevisiae RSC along double-stranded DNA. Biochemistry 2007, 46, 12416–12426. [Google Scholar] [CrossRef] [Green Version]
  92. Al-Ani, G.; Malik, S.S.; Eastlund, A.; Briggs, K.; Fischer, C.J. ISWI remodels nucleosomes through a random walk. Biochemistry 2014, 53, 4346–4357. [Google Scholar] [CrossRef]
  93. Morgan, A.M.; LeGresley, S.E.; Briggs, K.; Al-Ani, G.; Fischer, C.J. Effects of nucleosome stability on remodeler-catalyzed repositioning. Phys. Rev. E 2018, 97, 032422. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  94. Clapier, C.R.; Cairns, B.R. Regulation of ISWI involves inhibitory modules antagonized by nucleosomal epitopes. Nature 2012, 492, 280–284. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  95. Ludwigsen, J.; Klinker, H.; Mueller-Planitz, F. No need for a power stroke in ISWI-mediated nucleosome sliding. EMBO Rep. 2013, 14, 1092–1097. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  96. Udugama, M.; Sabri, A.; Bartholomew, B. The INO80 ATP-dependent chromatin remodeling complex is a nucleosome spacing factor. Mol. Cell. Biol. 2011, 31, 662–673. [Google Scholar] [CrossRef] [Green Version]
  97. Fyodorov, D.V.; Kadonaga, J.T. Dynamics of ATP-dependent chromatin assembly by ACF. Nature 2002, 418, 896–900. [Google Scholar] [CrossRef]
  98. He, X.; Fan, H.Y.; Narlikar, G.J.; Kingston, R.E. Human ACF1 alters the remodeling strategy of SNF2h. J. Biol. Chem. 2006, 281, 28636–28647. [Google Scholar] [CrossRef] [Green Version]
  99. Partensky, P.D.; Narlikar, G.J. Chromatin remodelers act globally, sequence positions nucleosomes locally. J. Mol. Biol. 2009, 391, 12–25. [Google Scholar] [CrossRef] [Green Version]
  100. Rippe, K.; Schrader, A.; Riede, P.; Strohner, R.; Lehmann, E.; Längst, G. DNA sequence-and conformation-directed positioning of nucleosomes by chromatin-remodeling complexes. Proc. Natl. Acad. Sci. USA 2007, 104, 15635–15640. [Google Scholar] [CrossRef] [Green Version]
  101. Manelyte, L.; Strohner, R.; Gross, T.; Längst, G. Chromatin targeting signals, nucleosome positioning mechanism and non-coding RNA-mediated regulation of the chromatin remodeling complex NoRC. PLoS Genet. 2014, 10, e1004157. [Google Scholar] [CrossRef] [Green Version]
  102. Winger, J.; Bowman, G.D. The Sequence of Nucleosomal DNA Modulates Sliding by the Chd1 Chromatin Remodeler. J. Mol. Biol. 2017, 429, 808–822. [Google Scholar] [CrossRef] [Green Version]
  103. Lequieu, J.; Schwartz, D.C.; de Pablo, J.J. In silico evidence for sequence-dependent nucleosome sliding. Proc. Natl. Acad. Sci. USA 2017, 114, E9197–E9205. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  104. Zhou, C.Y.; Johnson, S.L.; Lee, L.J.; Longhurst, A.D.; Beckwith, S.L.; Johnson, M.J.; Morrison, A.J.; Narlikar, G.J. The yeast INO80 complex operates as a tunable DNA length-sensitive switch to regulate nucleosome sliding. Mol. Cell 2018, 69, 677–688. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  105. Blossey, R.; Schiessel, H. Kinetic proofreading of gene activation by chromatin remodeling. HFSP J. 2008, 2, 167–170. [Google Scholar] [CrossRef] [PubMed]
  106. Narlikar, G.J. A proposal for kinetic proof reading by ISWI family chromatin remodeling motors. Curr. Opin. Chem. Biol. 2010, 14, 660–665. [Google Scholar] [CrossRef] [Green Version]
  107. Blossey, R.; Schiessel, H. Histone mark recognition controls nucleosome translocation via a kinetic proofreading mechanism: Confronting theory and high-throughput experiments. Phys. Rev. E 2019, 99, 060401. [Google Scholar] [CrossRef] [Green Version]
  108. Gregory, P.D.; Wagner, K.; Hörz, W. Histone acetylation and chromatin remodeling. Exp. Cell Res. 2001, 265, 195–202. [Google Scholar] [CrossRef]
  109. Clapier, C.R.; Nightingale, K.P.; Becker, P.B. A critical epitope for substrate recognition by the nucleosome remodeling ATPase ISWI. Nucleic Acids Res. 2002, 30, 649–655. [Google Scholar] [CrossRef]
  110. Längst, G.; Becker, P.B. Nucleosome remodeling: one mechanism, many phenomena? Biochim. Biophys. Acta-(Bba)-Gene Struct. Expr. 2004, 1677, 58–63. [Google Scholar] [CrossRef]
  111. Grunstein, M. Histone acetylation in chromatin structure and transcription. Nature 1997, 389, 349–352. [Google Scholar] [CrossRef]
  112. Turner, B.M. Histone acetylation and an epigenetic code. Bioessays 2000, 22, 836–845. [Google Scholar] [CrossRef]
  113. Kouzarides, T. Histone methylation in transcriptional control. Curr. Opin. Genet. Dev. 2002, 12, 198–209. [Google Scholar] [CrossRef]
  114. Bannister, A.J.; Schneider, R.; Kouzarides, T. Histone methylation: dynamic or static? Cell 2002, 109, 801–806. [Google Scholar] [CrossRef] [Green Version]
  115. Hamiche, A.; Kang, J.G.; Dennis, C.; Xiao, H.; Wu, C. Histone tails modulate nucleosome mobility and regulate ATP-dependent nucleosome sliding by NURF. Proc. Natl. Acad. Sci. USA 2001, 98, 14316–14321. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  116. Clapier, C.R.; Längst, G.; Corona, D.F.; Becker, P.B.; Nightingale, K.P. Critical role for the histone H4 N terminus in nucleosome remodeling by ISWI. Mol. Cell. Biol. 2001, 21, 875–883. [Google Scholar] [CrossRef] [Green Version]
  117. Dang, W.; Kagalwala, M.N.; Bartholomew, B. Regulation of ISW2 by concerted action of histone H4 tail and extranucleosomal DNA. Mol. Cell. Biol. 2006, 26, 7388–7396. [Google Scholar] [CrossRef] [Green Version]
  118. Ferreira, H.; Flaus, A.; Owen-Hughes, T. Histone modifications influence the action of Snf2 family remodelling enzymes by different mechanisms. J. Mol. Biol. 2007, 374, 563–579. [Google Scholar] [CrossRef] [Green Version]
  119. Racki, L.R.; Naber, N.; Pate, E.; Leonard, J.D.; Cooke, R.; Narlikar, G.J. The histone H4 tail regulates the conformation of the ATP-binding pocket in the SNF2h chromatin remodeling enzyme. J. Mol. Biol. 2014, 426, 2034–2044. [Google Scholar] [CrossRef] [Green Version]
  120. Makowski, M.; Grawe, C.; Foster, B.; Nguyen, N.; Bartke, T.; Michiel, V. Global profiling of protein–DNA and protein–nucleosome binding affinities using quantitative mass spectrometry. Nat. Commun. 2018, 9, 1–10. [Google Scholar] [CrossRef] [Green Version]
  121. Barbera, A.J.; Chodaparambil, J.V.; Kelley-Clarke, B.; Joukov, V.; Walter, J.C.; Luger, K.; Kaye, K.M. The nucleosomal surface as a docking station for Kaposi’s sarcoma herpesvirus LANA. Science 2006, 311, 856–861. [Google Scholar] [CrossRef]
  122. Kalashnikova, A.A.; Porter-Goff, M.E.; Muthurajan, U.M.; Luger, K.; Hansen, J.C. The role of the nucleosome acidic patch in modulating higher order chromatin structure. J. R. Soc. Interface 2013, 10, 20121022. [Google Scholar] [CrossRef] [Green Version]
  123. McGinty, R.K.; Tan, S. Recognition of the nucleosome by chromatin factors and enzymes. Curr. Opin. Struct. Biol. 2016, 37, 54–61. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  124. Dao, H.T.; Dul, B.E.; Dann, G.P.; Liszczak, G.P.; Muir, T.W. A basic motif anchoring ISWI to nucleosome acidic patch regulates nucleosome spacing. Nat. Chem. Biol. 2020, 16, 134–142. [Google Scholar] [CrossRef] [PubMed]
  125. Gamarra, N.; Johnson, S.L.; Trnka, M.J.; Burlingame, A.L.; Narlikar, G.J. The nucleosomal acidic patch relieves auto-inhibition by the ISWI remodeler SNF2h. Elife 2018, 7, e35322. [Google Scholar] [CrossRef] [PubMed]
  126. Bao, Y.; Shen, X. Chromatin Remodeling: INO80 and SWR1. Cell 2011, 144, 158–158.e2. [Google Scholar] [CrossRef] [Green Version]
  127. Turinetto, V.; Giachino, C. Multiple facets of histone variant H2AX: A DNA double-strand-break marker with several biological functions. Nucleic Acids Res. 2015, 43, 2489–2498. [Google Scholar] [CrossRef] [Green Version]
  128. Rudnizky, S.; Bavly, A.; Malik, O.; Pnueli, L.; Melamed, P.; Kaplan, A. H2A. Z controls the stability and mobility of nucleosomes to regulate expression of the LH genes. Nat. Commun. 2016, 7, 1–12. [Google Scholar] [CrossRef]
  129. Giaimo, B.D.; Ferrante, F.; Herchenröther, A.; Hake, S.B.; Borggrefe, T. The histone variant H2A. Z in gene regulation. Epigenetics Chromatin 2019, 12, 1–22. [Google Scholar] [CrossRef] [Green Version]
  130. Hada, A.; Hota, S.K.; Luo, J.; Lin, Y.C.; Kale, S.; Shaytan, A.K.; Bhardwaj, S.K.; Persinger, J.; Ranish, J.; Panchenko, A.R.; et al. Histone Octamer Structure Is Altered Early in ISW2 ATP-Dependent Nucleosome Remodeling. Cell Rep. 2019, 28, 282–294. [Google Scholar] [CrossRef] [Green Version]
  131. Moshkin, Y.M.; Chalkley, G.E.; Kan, T.W.; Reddy, B.A.; Ozgur, Z.; van Ijcken, W.F.; Dekkers, D.H.; Demmers, J.A.; Travers, A.A.; Verrijzer, C.P. Remodelers organize cellular chromatin by counteracting intrinsic histone-DNA sequence preferences in a class-specific manner. Mol. Cell. Biol. 2012, 32, 675–688. [Google Scholar] [CrossRef] [Green Version]
  132. Smeenk, G.; Wiegant, W.W.; Vrolijk, H.; Solari, A.P.; Pastink, A.; van Attikum, H. The NuRD chromatin–remodeling complex regulates signaling and repair of DNA damage. J. Cell Biol. 2010, 190, 741–749. [Google Scholar] [CrossRef]
  133. Polo, S.E.; Kaidi, A.; Baskcomb, L.; Galanty, Y.; Jackson, S.P. Regulation of DNA-damage responses and cell-cycle progression by the chromatin remodelling factor CHD4. EMBO J. 2010, 29, 3130–3139. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  134. Papamichos-Chronakis, M.; Watanabe, S.; Rando, O.J.; Peterson, C.L. Global Regulation of H2A.Z Localization by the INO80 Chromatin-Remodeling Enzyme Is Essential for Genome Integrity. Cell 2011, 144, 200–213. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  135. Polo, S.E. Reshaping chromatin after DNA damage: The choreography of histone proteins. J. Mol. Biol. 2015, 427, 626–636. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  136. LeGresley, S.E.; Wilt, J.; Antonik, M. DNA damage may drive nucleosomal reorganization to facilitate damage detection. Phys. Rev. E 2014, 89, 032708. [Google Scholar] [CrossRef] [PubMed]
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Figure 1. The first level of compacting the genome into chromatin involves wrapping the DNA around octamers of histone proteins to form nucleosomes. We identify in this figure a nucleosome core particle, which consists of an octamer of histone proteins wrapped by ≈147 basepairs of DNA. These nucleosome core particles are further wrapped together to form a structure known as a 30 nm fiber due to its physical dimensions. Supercoiling of the 30 nm fibers into chromatine loops then leads to the formation of a chromosome.
Figure 1. The first level of compacting the genome into chromatin involves wrapping the DNA around octamers of histone proteins to form nucleosomes. We identify in this figure a nucleosome core particle, which consists of an octamer of histone proteins wrapped by ≈147 basepairs of DNA. These nucleosome core particles are further wrapped together to form a structure known as a 30 nm fiber due to its physical dimensions. Supercoiling of the 30 nm fibers into chromatine loops then leads to the formation of a chromosome.
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Figure 2. Pictorial representation of the domains conserved within each subfamily of chromatin remodelers. The DExx and HELICc domains are common to all chromatin remodelers and are found within the catalytic ATPase subunit. The HSA domain, responsible for binding actin and actin-related proteins, is common to both SWI/SNF and INO80 chromatin remodelers, but only SWI/SNF chromatin remodelers possess a BROMO domain, which is involved in recognizing acetylated histone proteins. The HAND, SLIDE, and SANT domains are unique to ISWI chromatin remodelers and play roles in DNA and histone binding. Only CHD remodelers possess CHROMO domains that are involved in recognizing methylated histones.
Figure 2. Pictorial representation of the domains conserved within each subfamily of chromatin remodelers. The DExx and HELICc domains are common to all chromatin remodelers and are found within the catalytic ATPase subunit. The HSA domain, responsible for binding actin and actin-related proteins, is common to both SWI/SNF and INO80 chromatin remodelers, but only SWI/SNF chromatin remodelers possess a BROMO domain, which is involved in recognizing acetylated histone proteins. The HAND, SLIDE, and SANT domains are unique to ISWI chromatin remodelers and play roles in DNA and histone binding. Only CHD remodelers possess CHROMO domains that are involved in recognizing methylated histones.
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Figure 3. One model proposed for the repositioning of the nucleosome core particle involves the formation and propagation of DNA loops [49,53,65,67,87,88]. The propagation of these DNA loops relies upon the ability of the chromatin remodeler to translocate the nucleosomal DNA relative to the histone octamer.
Figure 3. One model proposed for the repositioning of the nucleosome core particle involves the formation and propagation of DNA loops [49,53,65,67,87,88]. The propagation of these DNA loops relies upon the ability of the chromatin remodeler to translocate the nucleosomal DNA relative to the histone octamer.
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Figure 4. The network of interactions between the DNA, histones, and the chromatin remodelers that influence nucleosome repositioning.
Figure 4. The network of interactions between the DNA, histones, and the chromatin remodelers that influence nucleosome repositioning.
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Table
Table 1. Subfamilies of chromatin remodelers.
Table 1. Subfamilies of chromatin remodelers.
SubfamilyPrinciple ActivityAdditional DomainsDomain Function
ISWINucleosome assembly and spacing
Transcription regulation		HAND, SANT, and SLIDEDNA and nucleosome binding
SWI/SNFTranscription regulationHSA
BROMO		Binds nuclear actin-related proteins
Recognizes acetylated histones
CHDInteracts with promoter DNA sequences
Transcription regulation		CHROMORecognizes methylated histones
INO80Inositol-responsive gene expression
Deposition of histone variant H2AZ		HSABinds actin and actin-related proteins
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Morgan, A.; LeGresley, S.; Fischer, C. Remodeler Catalyzed Nucleosome Repositioning: Influence of Structure and Stability. Int. J. Mol. Sci. 2021, 22, 76. https://doi.org/10.3390/ijms22010076

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Morgan A, LeGresley S, Fischer C. Remodeler Catalyzed Nucleosome Repositioning: Influence of Structure and Stability. International Journal of Molecular Sciences. 2021; 22(1):76. https://doi.org/10.3390/ijms22010076

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Morgan, Aaron, Sarah LeGresley, and Christopher Fischer. 2021. "Remodeler Catalyzed Nucleosome Repositioning: Influence of Structure and Stability" International Journal of Molecular Sciences 22, no. 1: 76. https://doi.org/10.3390/ijms22010076

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Morgan, A., LeGresley, S., & Fischer, C. (2021). Remodeler Catalyzed Nucleosome Repositioning: Influence of Structure and Stability. International Journal of Molecular Sciences, 22(1), 76. https://doi.org/10.3390/ijms22010076

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