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Regulation of ISWI-family of chromatin remodelling complexes Maria Toto*, Giulia D’Angelo*, Davide FV Corona Maria Toto, Giulia D’Angelo, Davide FV Corona Dulbecco Telethon Institute c/o University of Palermo Dpt STEBICEF-Viale delle Scienze - Edificio 16 90128-Palermo-Italy E-mail of the corresponding author: [email protected] Tel: +39 091 238 97345; Fax: +39 091 238 60721 *These authors contributed equally to this review Keywords (4 to 6): ISWI, nucleosome, chromatin remodelling, histone Abstract (150 to 250 words) The packaging of DNA into chromatin facilitates the storage of the genetic information within the nucleus but prevents the access to the underlying sequences. The evolutionarily conserved ISWI family of ATP-dependent chromatin remodelling complexes provide one of the regulatory mechanisms that eukaryotic cells have evolved to induce structural changes to chromatin. All ISWIcontaining complexes use the energy derived from ATP hydrolysis in order to rearrange nucleosomes on chromatin to carry specific nuclear reactions. The combination of associated proteins with the ATPase subunit as well as specific histone modifications specialize the nuclear function of each ISWI-containing complex. Here we review the many way through which ISWI enzymatic activity can be modulated and regulated in the nucleus of eukaryotic cells. Introduction Eukaryotic cells store their genetic information in the form of chromatin, a complex of DNA packed with structural and regulatory proteins. The functional repeating unit of chromatin is the nucleosome, 146 base pairs of DNA wrapped around an octamer of histone proteins. While this packaging provides the cell with the obvious benefit of organizing a large and complex genome in the nucleus, it can also block access to DNA. Nuclear reactions therefore depend on factors that modulate the accessibility of DNA within the context of chromatin. ATP-dependent chromatin remodeling and the covalent modification of histone amino termini, play central roles in determining chromatin accessibility [ref]. These reactions are catalyzed by evolutionarily conserved multi-subunit chromatinremodeling complexes that directly alter chromatin structure to regulate gene expression and other nuclear functions [ ref]. ISWI is a component of several ATP-dependent chromatin remodeling complexes conserved in composition and function across species [ ref] (FIG). In higher eukaryotes, ISWI is an abundant and ubiquitously expressed protein that is essential for cell viability [ ref]. ISWI chromatin remodellers are involved in important nuclear functions such as DNA replication, DNA repair, transcriptional regulation and chromosome structure maintenance [ref]. In order to modulate these essential biological processes, ISWI activity needs to be finely regulated. To date, work conducted in several model system has revealed a multitude of ways by which ISWI-chromatin remodelling activity can be regulated in the nucleus. Due to the broad spectrum of functions played by ISWI, several nucelar factors influence its function in order to integrate ISWI activity in different physiological contexts in vivo. Indeed, nucleosome spacing reactions catalyzed by ISWI can be regulated (1) in cis by intrinsic domains of ISWI protein, (2) by its associated subunits and other chromatin factors, (3) by post-translational modification of ISWI itself and of its associated nucleosomal substrate, (4) and finally by specific DNA and RNA sequence features. Here we present a review of the different mechanisms by which t ISWI enzymatic activity could be regulated in the nucleus of eukaryotic cells. (1) Allosteric regulation through structural and functional ISWI domains (add Fig) Regulation of ISWI chromatin remodelers targeting and activity on nucleosome substrates is essential to gain knowledge on chromatin dynamics. Since their discovery, different levels of regulation of ISWI chromatin remodelling activity emerged (Erdel, Krug et al. 2011). Although the auxiliary subunits of ISWI complexes greatly contribute to the regulation of its activity, recent work has shed light into the function of its intrinsic domains. Interestingly, studies conducted in Drosophila and in yeast, demonstrated that the conserved ATPase domain has autonomous nucleosome remodelling activity while the ATPase adjacent domains have a regulatory function (Clapier and Cairns 2012; Hota, Bhardwaj et al. 2013; Mueller-Planitz, Klinker et al. 2013). ISWI contains a highly conserved ATPase core domain located in the N-terminal half of the protein and a characteristic set of domains, HAND-SANT-SLIDE (HSS), at the C-terminal with DNAbinding function (Grune, Brzeski et al. 2003; Boyer, Latek et al. 2004; Hota and Bartholomew 2011). Over the past few years, in vivo and in vitro studies have led to a broadly accepted model in which the HSS domain plays an integral part during the remodelling reaction (Boyer, Langer et al. 2002; Grune, Brzeski et al. 2003; Boyer, Latek et al. 2004). Unexpectedly, a recent study showed that most of fundamental regulatory aspects of nucleosome remodelling are contained within the compact ATPase module of Drosophila ISWI. In this work the authors found that ISWI lacking its HSS domain can still remodel nucleosomes, with an intrinsic ability to bind nucleosomes and functionally interact with H4 N-terminus, revealing a positive role for the HSS domain in increasing the affinity and specificity of ISWI ATPase for nucleosome (Mueller-Planitz, Klinker et al. 2013). Similarly, another study showed a regulatory function for the SLIDE domain of Saccharomyces cerevisiae Isw2 subunit, to help maintaining the directionality of movement of DNA into nucleosomes (Hota, Bhardwaj et al. 2013). All together these data underline that the accessory domains of the ATPase core of ISWI may have evolved to optimize catalysis and modulate the outcome of the reaction. This idea was also supported by the identification of two new conserved and separate negative regulatory regions of the dISWI ATPase, defined as AutoN and NegC. The first is located within the N-terminus of ISWI ATPase and has a conserved sequence that resembles the basic patch of the H4 tail. NegC is located between the ATPase core and the HSS DNA-binding domain (Fig ?). AutoN inhibits the ATP-hydrolysis rate working as a brake that constrains the catalytic activity of ISWI by making contact with the ATPase lobes. NegC inhibits ATPase coupling to DNA translocation. Moreover, mutation of AutoN and NegC enables marked nucleosome sliding without the H4 basic patch, DNA linker, or the HSS domain, confirming that the ISWI ATPase core is an intrinsically active DNA translocase, flanked by specific regulatory modules that ensure remodelling only in the presence of proper nucleosomal epitopes (Clapier and Cairns 2013). An integrated view of these and other structural data obtained so far, imply that remodelernucleosome interactions stabilize a conformation of ISWI that is permissive for DNA translocation. On the basis of the characterization of AutoN and NegC inhibitory roles, this conformational change probably involves removal of both of these ATPase brakes (Manning and Peterson 2013). Very recently, the C-terminal portion of ISWI emerged ad a relevant regulatory domain, playing an important role in the nuclear import of the remodelling enzyme. While it has been previously shown that the import of hSNF2H, one of the human ISWI homolog [ref], to the nucleus is controlled by the accessory subunits of the complex (Sheu, Choi et al. 2008; Lan, Ui et al. 2010), in a very recent study I has been shown that the nuclear import of S. cerevisiae Isw1 is mediated by a specific nuclear localization signal (NLS) located at the end of the C-terminal partion (aa10079-1105) [ref]. In vitro binding assay of Isw1-NLS to importin- revealed that the nuclear translocation of Isw1 is mediated by the classical import pathway. Moreover this mechanism was recognized as the solely regulator of the remodeler nuclear translocation in vivo. Interestingly, similar nuclear localization motif were identified in silico in ISWI orthologues of higher eukaryotes, suggesting that the Ctermini of the ISWI family proteins play an important role in their nuclear import (Vasicova, Stradalova et al. 2013). (2) ISWI chromatin remodelers regulation by protein-protein interaction (add Fig) The enzymatic activity of ISWI chromatin remodelling complexes resides within their catalytic ATPase subunit, but its associated subunits can modulate its activity therefore representing an additional level of regulation of ISWI chromatin remodelling reactions. Since the discovery that ISWI alone, out if the context of its associated subunits, has nucleosome remodelling activity (Corona et al Mol cell 1999), at least two principal roles have been recognized for the accessory subunits: (1) the modulation of nucleosome remodelling reactions and(2) the targeting of the remodeling complex to the specific chromatin regions. The first subunits able to regulate ISWI nucleosome remodelling activity to be identified were Drosophila ACF1 and NURF301. Both ACF1 and NURF301 can modulate ISWI enzymatic functions via their PHD finger domains that provide an anchor point to the nucleosome (Aasland, Gibson et al. 1995; Eberharter, Vetter et al. 2004; Strohner, Wachsmuth et al. 2005; Wysocka, Swigut et al. 2006). In particular, in the ACF and CHRAC complexes, the ACF1 subunit strongly increases the ability of ISWI to assemble chromatin (Ito, Levenstein et al. 1999), and its nucleosome sliding efficiency (Eberharter, Ferrari et al. 2001; Eberharter, Vetter et al. 2004). The association of ISWI with ACF1 or NURF301 subunits is also able to determine the biochemical properties of the ACF/CHRAC and NURF complexes. In fact, while ISWI alone catalyzes the movement of a nucleosome toward the end of short DNA fragment, the ACF complex catalyzes the movement of nucleosome toward the central portion of the same DNA fragment (Langst, Bonte et al. 1999; Brehm, Langst et al. 2000; Eberharter, Ferrari et al. 2001). Similarly, in the NURF complex, the NURF301 subunit modifies the intrinsic nucleosome mobilization proprieties of ISWI and interacts with sequence-specific transcription factors, targeting NURF complex to specific genes (Xiao, Sandaltzopoulos et al. 2001). In a similar way, also the non-catalytic subunits associated with human SNF2H complexes (hACF, hRSC, hCHRAC and WICH) regulate SNF2H ATPase ability to interact and remodel nucleosomes through their interaction with the linker DNA emerging from nucleosome (He, Fan et al. 2008). The regulative role played by the accessory subunit of ISWI complexes was recently also described for the novel evolutionary conserved ISWIcontaining complex ToRC. In ToRC complex all three subunits (TIP5/tou, ISWI, CtBP) are indeed required for its maximal biochemical activity (Emelyanov, Vershilova et al. 2012). Regulation by histones and post-translational modifications (add Fig) Histone modifications Histone tail domains are targeted by modifying enzymes responsible for their methylation, acetylation, phosphorylation, ADP-ribosylation, and ubiquitination (Wu and Grunstein 2000; Berger 2002; Bannister and Kouzarides 2011). Histone modifications not only directly regulate chromatin structure by changing the interaction between the octamer and the DNA, but most importantly by regulating remodelling enzymes chromatin targeting (Strahl and Allis 2000). The ability to recognize histone modifications constitutes an integral part of all ATP-dependent chromatin complexes that may either help the targeting of the enzymes to particular genomic sites and/or modulate their activities. Particularly, the ISWI ATPase and its regulatory subunits posses dedicated domains that specifically interact with unmodified and modified histone tails. In fact, one of the peculiarities of ISWI remodelling enzymes is that they require the binding of H4 tail for substrate recognition and efficient remodelling activity. Many studies in flies highlighted that the DNA-bound basic patch of H4 is an epitope specifically bound by the SANT domain in ISWI ATPase and that the state of acetylation of adjacent lysine residues, as K12 and K16, can negatively influence the remodeler functions, like in the case of dNURF complex (Clapier, Langst et al. 2001; Hamiche, Kang et al. 2001; Clapier, Nightingale et al. 2002; Corona, Clapier et al. 2002). Also in yeast it has been demonstrated that the remodelling activity of Iswi2 is influenced by acetylation of H4K16. This modification indeed decreases the catalytic rate of ATP hydrolysis, confirming that unmodified H4 tail acts as an allosteric activator of the ATPase (Ferreira, Flaus et al. 2007) that is important both for chromatin compaction and nucleosome remodelling by ISWI (Zhou, Feng et al. 2012). Furthermore, the ISWI containing complexes can also recognize the methylated histones thanks the PHD finger domain present in the ISWI associated subunits. For example, the trimethylated H3K4 is a histone post-translational modification with a regulatory role in the recruitment of ISWI complexes. This substrate is bound by the PHD finger domain in BPTF subunit of NURF complex (Wysocka, Swigut et al. 2006). Also in yeast, it has been shown that di- or trimethylation of the histone H3K4 is specifically required for the recruitment of Isw1 and for the correct repositioning of RNA pol II in the coding regions (Santos-Rosa, Schneider et al. 2003). In addition, regulatory roles regarding the phosphorylation of histones were also highlighted. In Xenopus laevis there are evidences that xISWI complexes regulation during mitosis is under the control of the INCENP-aurora B kinase complex that phosphorylates serine 10 of histone H3 (MacCallum, Losada et al. 2002). Histone variants ISWI remodelers recognize the modified histone tails in nucleosomes, as well as the globular regions of the histone proteins. Besides the canonical core histones, there are several histone variants that are incorporated into chromatin in a regulated manner and several classes of chromatin remodelers, including ISWI subfamily, are known to be involved in incorporation and stabilization of histone variants into the core of histonic octamer (Mizuguchi, Shen et al. 2004; Konev, Tribus et al. 2007; Okada, Okawa et al. 2009; Perpelescu, Nozaki et al. 2009). Particularly, H2A.Z, an H2A variant shown to be enriched at transcriptional control regions, it has been found to increase the nucleosome activity of the hISWI (sostituire con SNF2h ? o Snf2l ? qual’e’ coinvolta ?) in vitro (Goldman, Garlick et al. 2010). Another works conducted in vivo on hRSF, demonstrated that this remodeler is able to govern the replacement of H2Av in the pathway of silent chromatin formation (Hanai, Furuhashi et al. 2008). Contradictory data exist about the role of macroH2A: whereas in some works it has been demonstrated that this variant specifically interferes with ACF and SWI/SNF nucleosome remodelling (Angelov, Molla et al. 2003; Doyen, Montel et al. 2006) and in a recent study it was demonstrated that macroH2A has a negative effect on the recruitment and remodelling activity only of SWI/SNF (Chang, Ferreira et al. 2008). Another example of how histone variants can regulate ISWI remodeler mode of action is represented by H2A.X variant. This non-canonical histone, bind strongly than H2A to WICH complex and it has been shown to be important in its recruitment to DNA repair sites (Xiao, Li et al. 2009). ISWI posttranslational modifications A further regulatory strategy of ISWI chromatin remodelers involves the direct post-translational modification of the enzyme by specific proteins such as histone acetyl-transferase and poly-ADPribose polymerase. While it has been extensive documented the fact that the Gcn5 protein acts as an histone acetyltransferase by targeting the H3K14 (Wang, Mizzen et al. 1997), the pioneering work of Ferreira and colleagues identified and characterized for the first time in vitro and in vivo the acetylation of dISWI ATPase by GCN5 at the conserved lysine 753 located in the HAND domain. This study and other unpublished observations mentioned within, suggested that the acetylation of ISWI is an early development regulated process probably linked to the expression of selected Drosophila genes (Ferreira, Eberharter et al. 2007). Interestingly, in vivo and in vitro investigations demonstrated that dISWI is also target of the PARP enzyme, an abundant nuclear protein that transfer ADP-ribose to proteins important for DNA transcription, repair and for chromatin structure. ISWI –PARP interactions was detected for the first time in an unbiased genetic screens aimed to identifying factors modifying phenotypes caused by loss of ISWI function. These screens provided the first genetic interaction map of potential regulators of ISWI in the higher eukaryote Drosophila melanogaster .(Burgio, La Rocca et al. 2008; Arancio, Onorati et al. 2010). Parylated dISWI displays a reduction in both nucleosome binding affinity and in ATPase activity. Further, parylated ISWI tends to dissociate from its chromatin target sites, suggesting that Poly ADP-ribosylation counteracts ISWI functions, in vitro and in vivo (Sala, La Rocca et al. 2008). While the phosphorylation of ATPase subunit of the hSWI/SNF remodelling complex was the first example of phospho-regulation of a remodeler to have been documented, a regulation of ISWI-type chromatin remodeling complexes by phosphorylation has not yet been highlighted. Nevertheless work conducted by Oya and collegues, documented that the mammalian WSTF protein, a subunit of two chromatin remodelling complexes (SWI/SNF type WINAC and ISWI-type WHICH), is specifically phosphorylated at serine 158 by the stimulation of MAPK cascade in vitro and in vivo. This modification has been demonstrated to be fundamental in finely tuning the balance between the two WSTF containing complexes, involved in various nuclear event (Oya, Yokoyama et al. 2009). (4) Regulation of ISWI chromatin remodelling activity by nucleic acids (add Fig) DNA Both the ISWI ATPase motor protein and its associated subunits contain DNA-binding motifs. Thus, this raises the question whether DNA sequence influences chromatin remodelling activity catalyzed by ISWI. Numerous in vitro studies have shown that the DNA sequence and conformation is relevant for the outcome of the remodelling reaction (Stockdale, Flaus et al. 2006; Rippe, Schrader et al. 2007). For instance, the remodelling reaction of the ISWI-type complex ACF requires a short DNA element, with high intrinsic curvature, that determine ACF-dependent nucleosome position (Rippe, Schrader et al. 2007). Moreover, a recent work suggested a mechanism by which the DNA sequence cooperates with human remodeler ACF to switch nucleosomes between two different locally meaningful positions based on environmental stimuli (Partensky and Narlikar 2009). The DNA sequence feature role on the ISWI chromatin remodelling activity was recently suggested also by genome-wide studies (Moshkin, Chalkley et al. 2012). Moreover, motif discovery analysis, based on ISWI-associated sequences, suggests that dISWI preferentially bind specific DNA consensus motifs, supporting the potential regulatory role played by underlying DNA sequence in the targeting of ISWI to specific chromatin loci (Sala, Toto et al. 2011). Linker DNA also has an effect on the ISWI remodelling. Whereas previous work paid little attention whether the length of extra-nucleosomal DNA could be an important factor for remodelling activity, the ISWI subfamily remodelers were the first to have shown a strong dependence on linker DNA length (Zofall, Persinger et al. 2004). In particular, a drammatic reduction in ISWI catalytic activity and nucleosome binding it has been documented when the linker DNA was shortened (Kagalwala, Glaus et al. 2004; Zofall, Persinger et al. 2004; Dang, Kagalwala et al. 2006; Stockdale, Flaus et al. 2006; Yang, Madrid et al. 2006). These observations highlighted that the ISWI ATPase makes more extensive contacts with the linker DNA when is in an activated ATP state compared to the inactivated state. However, until now it remains unclear which step of the ATPase hydrolysis cycle the flanking DNA participates in. An additional level of complexity is to distinguish the direct and indirect effects of DNA. Several subunits of ISWI complexes interact with linker DNA forming an integral part of the machinery that modulate the binding and activity of the ISWI ATPase domain. In yIsw2 the accessory subunit Itc1 extensively interacts with at least 53 bp of extranucleosomal DNA (Kagalwala, Glaus et al. 2004). In agreement with this, a very recent study conducted in yeast, suggested that enrichment of yIsw1 at nucleosome-depleted regions (NDRs) is favoured by the transcription factors. Particularly, in this work Zentner et al. suggested that TFs binding generate extended linker DNA regions which enabling an efficient association between yIsw1 and its binding site (Zentner, Tsukiyama et al. 2013). Similarly, dCHRAC and hCHRAC complexes contain two additional histone-fold proteins which enhance sliding activity mediate by ACF, probably by binding and bending the DNA emerging from the nucleosome (Kukimoto, Elderkin et al. 2004; McConnell, Gelbart et al. 2004; Hartlepp, Fernandez-Tornero et al. 2005). A similar mechanism has been observed by the high mobility group (HMG) proteins which cooperate with ISWI chromatin remodelling complexes in the increase their capacity to bind nucleosomal DNA and enhance their sliding activity (Xiao, Sandaltzopoulos et al. 2001; Bonaldi, Langst et al. 2002). Therefore, since the ISWI nucleosome remodelling regulation involves the alteration of the flanking DNA at and around the nucleosome and since the accessory subunits interact with DNA, discern each role is very difficult. RNA Another possible regulatory role of ISWI could be ascribed to RNA molecules. Indeed RNA, as DNA, may represent a binding signal for ISWI chromatin remodelers. One example has been shown for NoRC remodelling complex interaction with RNA. The RNA-NoRC interaction has been found to be crucial for targeting the chromatin-remodelling complex to the nucleolus (Mayer, Neubert et al. 2008). Moreover in vivo and in vitro interaction between the ATPase Drosophila (Onorati, Lazzaro et al. 2011). Further, very recently the miR-99a was found to regulate the expression of Snf2h altering the efficiency of DNA repair (Mueller, Sun et al. 2013) Conclusions Despite the simplicity of the nucleosome spacing reaction catalized by ISWI, its activity is highly regulated and essential to support a variety of nuclear reactions that need nucleosomal accessibility. Genetic and biochemical studies have provided a wealth of data concerning the mechanisms of regulation of ISWI in different model systems. 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