Eukaryotic chromatin is decorated with a wide range of reversible histone post-translational modifications (PTMs) that regulate all processes that require access to DNA, including transcription, DNA replication and DNA repair (Bannister and Kouzarides, 2011; Bowman and Poirier, 2015). Actively transcribed genes in all eukaryotes are enriched in monoubiquitinated histone H2B, which plays a non-degradative role in promoting transcription (Fleming et al., 2008; Weake and Workman, 2008) but whose mechanism of action remains poorly understood. Monoubiquitin is conjugated to H2B-K123 in yeast and H2B-K120 in humans, which lie near the C-terminus of histone H2B (Robzyk et al., 2000; Weake and Workman, 2008; West and Bonner, 1980). Monoubiquitination of histone H2B is highly dynamic (Henry et al., 2003), and the cycle of ubiquitination and subsequent deubiquitination is an important checkpoint for transcription elongation (Batta et al., 2011). H2B-K123 ubiquitination is required for methylation of histone H3K4 (Chandrasekharan et al., 2010; Dover et al., 2002) and H3K79 (Ng et al., 2002), two other marks correlated with actively transcribed genes. However, H2B-Ub also plays a role in promoting transcription that is independent of cross-talk with histone H3 methylation (Tanny et al., 2007). In addition to its role in transcription, H2B-Ub plays a role in replication fork progression, nucleosome assembly during DNA replication (Ng et al., 2002) and the DNA damage response (Giannattasio et al., 2005; Moyal et al., 2011; Uckelmann and Sixma, 2017). Dysregulation of histone H2B monoubiquitination has been linked to a variety of cancers (Cole et al., 2015; Espinosa, 2008; Hahn et al., 2012).

In the yeast, Saccharomyces cerevisiae, histone H2B-K123 is monoubiquitinated by the E2/E3 pair, Rad6/Bre1 (Hwang et al., 2003; Robzyk et al., 2000; Wood et al., 2003), and deubiquitinated by two deubiquitinating enzymes (DUBs): Ubp8 and Ubp10 (Daniel et al., 2004; Gardner et al., 2005; Henry et al., 2003). Both of these DUBs belong to the Ubiquitin Specific Protease (USP) class of cysteine proteases, which contain a characteristic USP catalytic domain (Komander et al., 2009). Ubp10 is a monomeric enzyme whereas Ubp8 is part of a four-protein subcomplex within the SAGA complex called the DUB module, which comprises Ubp8, Sgf11, Sus1, and Sgf73 (Henry et al., 2003; Köhler et al., 2010; Samara et al., 2010). Both yeast H2B-Ub DUBs are conserved in humans. USP36, the human homologue of Ubp10, can complement the effects of a ubp10 deletion on global H2B-Ub in yeast (Reed et al., 2015) and USP22, the homologue of Ubp8, is a subunit of human SAGA (Zhang et al., 2008). Yeast in which both Ubp10 and Ubp8 have been deleted showed a synergistic increase in the steady-state levels of global H2B-Ub, as well as growth defects (Emre et al., 2005). While the roles of Ubp10 and Ubp8 in regulating H2B deubiquitination are well-established, their respective contributions to chromatin-mediated processes are poorly understood.

Despite their shared substrate specificity, Ubp8 and Ubp10 appear to play distinct roles in vivo. Several studies have shown that SAGA/Ubp8 primarily acts on H2B-Ub near promoters and transcription start sites to promote transcription initiation by RNA polymerase II (Batta et al., 2011; Daniel et al., 2004; Schulze et al., 2011). Ubp10 was first identified for its role in regulating sub-telomeric gene silencing (Emre et al., 2005; Gardner et al., 2005; Kahana and Gottschling, 1999) and is recruited to silenced chromatin (Gardner et al., 2005). However, deletion of UBP10 alters expression of hundreds of yeast genes as well as H2B ubiquitination genome-wide (Gardner et al., 2005; Orlandi et al., 2004; Schulze et al., 2011), indicating that Ubp10 plays a global role beyond its function in subtelomeric transcriptional repression. Deletion of UBP8 also alters transcription of several hundred genes (Gardner et al., 2005), although an analysis of the data shows little correlation between the genes whose expression is impacted by ubp8 versus ubp10 deletion (Figure 1). The different impacts on transcription profiles suggest that these two H2B-Ub DUBs have distinct genomic targets. However, SAGA/Ubp8 was recently shown to be involved in transcription of all RNA polymerase II genes (Baptista et al., 2017; Warfield et al., 2017) and Ubp10 has been found in association with RNA polymerase II (Mao et al., 2014), suggesting that both DUBs may at least be present at all genes. A partial resolution of this conundrum comes from a genome-wide ChIP-on-chip study of H2B-Ub in ubp10 and ubp8 deletion strains (Schulze et al., 2011) which shows that loss of UBP8 results in an enrichment of H2B-Ub primarily near transcription start sites (TSS), whereas a ubp10 deletion strain shows broader enrichment of H2B-Ub in mid-coding regions of longer transcription units. The ChIP results suggest that Ubp8 and Ubp10 are required during transcription, but at different times and in different genic locations. However, it remains unclear how each of these factors produces these distinct profiles and what roles each enzyme plays during these processes.

Figure 1

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Ubiquitination of histone H2B has been reported to assist recruitment of the histone chaperone, FACT (Facilitates Chromatin Transcription) to active chromatin (Fleming et al., 2008). The yeast FACT complex is composed of a heterodimer of Spt16 and Pob3 that is assisted in vitro and in vivo by the DNA binding protein, Nhp6 (Brewster et al., 1998; Ruone et al., 2003; Schlesinger and Formosa, 2000; Wittmeyer and Formosa, 1995; Wittmeyer et al., 1999). FACT is reported to evict H2A/H2B heterodimers in front of the transcription machinery (Reinberg and Sims, 2006) and reassemble the heterodimers in the wake of RNA polymerase II to prevent cryptic transcription initiation (Fleming et al., 2008; Martin et al., 2018; Mason and Struhl, 2003; Pavri et al., 2006). The disruption of the H2B ubiquitination cycle or a mutation in the FACT subunit, Spt16, causes a defect in Pol II elongation (Fleming et al., 2008). In addition to roles in transcription, FACT and H2B-Ub are each also implicated in DNA replication (Formosa, 2012; Kurat et al., 2017; Trujillo and Osley, 2012). H2B-Ub at replication origins is thought to stabilize the parental nucleosomes after the passage of DNA polymerase (Trujillo and Osley, 2012). FACT and H2B-Ub play an important role in the progression of DNA replication, likely by maintaining chromatin stability and orchestrating nucleosome assembly on newly-synthesized DNA (Lin et al., 2014; Trujillo and Osley, 2012). It is clear that both FACT and H2B-Ub play a pivotal role in stabilizing and assembling nucleosomes in the wake of polymerases during replication and transcription. However, it is not known how FACT and H2B-Ub status affect one another to perform these functions.

We report here a novel role for the histone chaperone, FACT, in stimulating the H2B deubiquitination activity of Ubp10 on nucleosomes. We show that the rate of deubiquitination of yeast H2B-Ub is slower when incorporated into nucleosomes as compared to free H2A/H2B-Ub heterodimers, but that the addition of FACT reverses this block. This behavior is in marked contrast to the Ubp8/DUB module, which has robust activity on both heterodimers and intact nucleosomes and is not affected by FACT (Morgan et al., 2016). We show that a yeast strain with a FACT deficiency has elevated levels of H2B-Ub, indicating that FACT also stimulates deubiquitination of H2B in vivo. Deleting Ubp10, but not Ubp8, from a strain with mutated FACT conferred strong sensitivity to the DNA replication toxin, hydroxyurea (HU), and activated a cryptic transcription reporter. Our findings suggest that the differential effects of Ubp10 and Ubp8 on the distribution of H2B-Ub result from a global role for Ubp10 and FACT versus a local role of Ubp8/SAGA at promoters and transcription start sites. These observations have important implications for the way in which cycles of H2B ubiquitination and deubiquitination regulate nucleosome dynamics during transcription and DNA replication.

We have discovered a previously uncharacterized synergy between the H2B deubiquitinating enzyme, Ubp10, and the histone chaperone, FACT, that suggests a unifying model for the role of H2B ubiquitination and deubiquitination in nucleosome dynamics. The role of H2B monoubiquitination in recruiting FACT to nucleosomes and the importance of both FACT and H2B-Ub in transcription (Batta et al., 2011; Fleming et al., 2008; Weake and Workman, 2008) and in DNA replication (Lin et al., 2014; Trujillo and Osley, 2012), are well-established. However, the interplay between nucleosome dynamics, H2B deubiquitination and histone chaperones had not been explored. In this study, we report a role for the histone chaperone, FACT, in deubiquitinating H2B-Ub and show that Ubp10 depends on FACT to efficiently cleave H2B-Ub from nucleosomes (Figure 2). This behavior is unlike Ubp8/SAGA, which does not require FACT to deubiquitinate nucleosomes (Morgan et al., 2016). Consistent with our in vitro results, we find that a mutation that decreases the level of FACT (pob3-L78R) results in increased levels of H2B-Ub that are comparable to those caused by loss of Ubp10 (Figure 4). We also show that combining FACT mutations with loss of Ubp10, but not loss of Ubp8, causes sensitivity to hydroxyurea, suggesting a role for the FACT-Ubp10 collaboration in DNA replication. Similarly, combining FACT mutations with deletion of UBP10, but not UBP8, activates a cryptic promoter reporter gene, reflecting a role for Ubp10 in maintaining nucleosome occupancy during transcription. These combined in vivo and in vitro observations point to a role for Ubp10 and FACT in jointly maintaining chromatin organization and have important implications for the different cellular roles of the two H2B-Ub DUBs, Ubp8 and Ubp10.

Our results are consistent with a model in which Ubp10 plays a global role in regulating nucleosome dynamics in concert with FACT, while Ubp8 plays a more restricted role at sites of transcription initiation. This view is consistent with previous observations that Ubp8 deletion leads to higher levels of H2B-Ub in the vicinity of the +1 nucleosome, whereas Ubp10 deletions exhibit broader enrichment of H2B-Ub in gene bodies, particularly in longer open reading frames (Schulze et al., 2011). Ubp8 is targeted to genes in the context of the SAGA complex, a global transcription factor that associates with promoter regions of virtually all RNA polymerase II genes (Baptista et al., 2017; Baptista et al., 2018; Bonnet et al., 2014; Venters et al., 2011), which accounts for the observed pattern of H2B-Ub enrichment in ubp8 deletion strains (Schulze et al., 2011). The genome-wide pattern of H2B-Ub enrichment found in ubp10 deletion strains (Schulze et al., 2011) can be explained by a global function for Ubp10 in nucleosome assembly through its partnership with FACT. FACT has been implicated in transcription through its increased association with frequently transcribed genic regions (Feng et al., 2016; Mayer et al., 2010; Pathak et al., 2018; Saunders et al., 2003), but these same studies show that it is also abundant in intergenic regions. FACT physically interacts with both the MCM replicative helicase and with DNA polymerase α, and it promotes rapid deposition of nucleosomes in an in vitro replication system (Wittmeyer and Formosa, 1997; Yang et al., 2016; Yeeles et al., 2017). FACT is found in yeast cells at about two-thirds the abundance of nucleosomes and therefore is a global component of chromatin that participates in a broad range of chromatin-dependent processes (Gurova et al., 2018). These roles include restoring chromatin integrity after disruptions like transcription (Martin et al., 2018) but emerging evidence shows that FACT may have a less prominent role in proliferation of differentiated mammalian cells (Gurova et al., 2018; Shen et al., 2018). Collectively, these findings suggest, instead, that the primary role of FACT is to stabilize or maintain existing global chromatin architectures and promote transitions to new patterns during differentiation. The finding that Ubp10, but not Ubp8, plays an unanticipated role in DNA replication (Figures 4 and 5) and suppression of cryptic transcription (Figure 6) that overlaps with the role of FACT supports the idea that, like FACT, Ubp10 has a global function in maintaining stable chromatin architecture against a range of potential perturbations.

H2B ubiquitination has been proposed to stabilize chromatin as judged by a genome-wide reduction in nucleosome occupancy seen in mutants that lack Rad6, the E2 that ubiquitinates H2B, or in which wild type H2B is replaced by H2B-K123A, which cannot be ubiquitinated (Batta et al., 2011). Deletion of UBP8 enhances nucleosome occupancy genome-wide. However, the simple model that high global levels of H2B-Ub correlate with higher nucleosome occupancy is contradicted by the observation that highly transcribed genes have normal levels of nucleosome occupancy in a ubp8∆ mutant, even though these genes have markedly lower nucleosome occupancy in rad6∆ and H2B-K123A mutants (Batta et al., 2011). Our finding that a double ubp10∆/spt16-11 mutant activates a cryptic promoter points to a unique role for Ubp10 acting in concert with FACT to maintain nucleosome organization and is consistent with prior studies that suggest that cycles of both ubiquitination and deubiquitination are critical for nucleosome assembly during transcription (Batta et al., 2011; Fleming et al., 2008; Henry et al., 2003; Pavri et al., 2006).

In addition to its role in regulating global levels of H2B-Ub, Ubp10 regulates spreading of heterochromatic silencing at telomeres and at mating type loci (Emre et al., 2005; Gardner et al., 2005). This function is mediated by the N-terminus of Ubp10, which is recruited by the SIR complex to subtelomeric regions (Emre et al., 2005; Gardner et al., 2005; Zukowski et al., 2018). The silencing and global H2B ubiquitination functions of Ubp10 appear to be separable, as expression of N-terminal truncations of Ubp10 can restore wild type levels of H2B ubiquitination without restoring subtelomeric silencing (Reed et al., 2015). A recent study (Zukowski et al., 2018) reported that Sir2/Sir4, a subset of the SIR complex, stimulates the activity of GST-Ubp10 on both human nucleosomes and H2A/H2B-Ub heterodimers containing a hydrolyzable non-native linkage between ubiquitin and H2B. The observed stimulation was attributed to the ability of Sir2/Sir4 to recruit Ubp10 to chromatin, as has also been observed in vivo (Emre et al., 2005), as well as to a proposed allosteric stimulation of Ubp10 on both H2A/H2B-Ub heterodimers and on ubiquitinated nucleosomes (Zukowski et al., 2018). The effect observed in that study depended on residues 109–133 of Ubp10, which do not play a role in either Ubp10 catalytic activity on yeast H2A/H2B-Ub heterodimers, the ability to be stimulated by FACT (Figure 3), or FACT function in vivo (Figure 6—figure supplement 1). The effect of Sir2/Sir4 on Ubp10 thus appears to be restricted to its silencing-specific functions. Notably, human Usp15 also preferentially deubiquitinates H2A/H2B-Ub dimers and is stimulated by the splicing factor SART3 (Long et al., 2014), although in this case SART3 has the inverse effect: it enhances the activity of Usp15 on H2A/H2B-Ub but not on nucleosomes.

It is not clear why nucleosomes are such a poor substrate for Ubp10 as compared to H2A/H2B-Ub heterodimers. Ubp8 is targeted to nucleosomes in the context of the SAGA DUB module, in which Ubp8 forms a complex with Sgf11, Sus1 and Sgf73 (Henry et al., 2003; Köhler et al., 2010). The specificity of Ubp8 for H2B-K123 is conferred by Sgf11, which has a zinc finger domain with an arginine-rich patch (Köhler et al., 2010; Samara et al., 2010) that docks in the nucleosome acidic patch between histones H2A and H2B (Morgan et al., 2016). By contrast, Ubp10 is a monomeric enzyme that lacks accessory proteins that could promote binding to nucleosomes. However, Ubp10 has surprisingly high affinity for nucleosomes, binding with an apparent Kd of ~400 nM (Figure 3B). The wild-type Ubp8/DUB module, by contrast, does not bind detectably to nucleosomes by EMSA (Figure 3—figure supplement 3). The ability of Ubp10 to bind nucleosomes and the stimulation of Ubp10 enzymatic activity by FACT do not seem to be connected, as N-terminal deletions of Ubp10 that impair nucleosome binding are still stimulated by FACT (Figure 3B–D). Moreover, deletions within the N-terminal unstructured region of Ubp10 (Reed et al., 2015), which include residues important for recruitment to telomeres by the SIR complex (Kahana and Gottschling, 1999), have little or no effect on global H2B ubiquitination (Gardner et al., 2005). The significance of the ability of Ubp10 to bind nucleosomes, which was also observed by Zukowski et al. (2018), and the use of nucleosomes as substrates for deubiquitination therefore remains unresolved.

How does FACT stimulate the activity of Ubp10 on nucleosomes? While there is no direct evidence that FACT and Ubp10 work together in vivo, the synthetic genetic interaction and the biochemical cooperation that we observe is consistent with such a possibility. We propose that the structural changes that occur in canonical nucleosomes upon FACT binding are likely key to addressing this question, as the observed stimulation is specific to nucleosomal substrates. FACT can reorganize the nucleosome by disrupting histone/DNA contacts, leaving the nucleosome in an ‘open’ or ‘destabilized’ state (Chen et al., 2018; Kemble et al., 2015; McCullough et al., 2011) and by fully displacing H2A/H2B heterodimers (Belotserkovskaya et al., 2003; Chen et al., 2018; Hsieh et al., 2013; Orphanides et al., 1999; Wang et al., 2018; Xin et al., 2009). The most straightforward explanation for the effect of FACT on Ubp10 activity is therefore that FACT increases H2B deubiquitination by evicting H2A/H2B-Ub heterodimers, which are an excellent substrate for Ubp10 (Figures 2A and 3C). However, H2A-H2B displacement has been estimated to be limited to 20–50% of the total heterodimers (Orphanides et al., 1998; Xin et al., 2009) and requires the addition of Nhp6 to yeast Spt16-Pob3, whereas we observe complete deubiquitination, and no requirement for Nhp6. Dimer displacement can therefore only partially explain the effect of FACT. While it is not known whether ejected H2A/H2B heterodimers retain the H2B-K123 ubiquitin modification in vivo, our in vitro results clearly show that an H2A/H2B-Ub dimer bound to FACT can be rapidly deubiquitinated by Ubp10. Alternatively, FACT may stimulate Ubp10 by partly unwinding the DNA (Kemble et al., 2015; McCullough et al., 2011; Valieva et al., 2016), generating a hexasome, or yielding some other intermediate in nucleosome disassembly that either exposes surfaces that allow Ubp10 to interact more favorably with the H2B-Ub linkage or relieves steric clashes. In this second scenario, Ubp10 deubiquitinates H2B only after FACT has begun to destabilize the nucleosome, but without complete eviction of the dimer. In support of this idea, we find that the nucleosomes are intact following deubiquitination by Ubp10 (Figure 2—figure supplement 4). In either scenario, Ubp10 must deubiquitinate H2B-Ub at some point between the time the nucleosome is destabilized and before it is reassembled in the wake of either DNA or RNA polymerase. We think it is unlikely that FACT stimulates Ubp10 by recruiting it to the nucleosome, as we see no evidence that FACT enhances Ubp10 binding (Figure 3B and Figure 3—figure supplement 2). The enhancement of Ubp10 activity provides the first example of a physiologically relevant substrate that appears to be activated by FACT-mediated destabilization of nucleosomes. Further studies will be needed to unravel the molecular determinants governing Ubp10 substrate preference as well as the mechanism by which FACT activates deubiquitination of nucleosomes.

The coupling of Ubp10 and FACT activity provides a missing link between cycles of H2B ubiquitination and deubiquitination, and FACT activity and nucleosome disassembly and assembly that allows us to propose a global model for the role of H2B ubiquitination in chromatin dynamics (Figure 7). Ubiquitination of H2B by Rad6/Bre1 recruits FACT, which can either facilitate nucleosome disassembly or bind to nucleosomes that are already destabilized. Ubp10 then deubiquitinates H2B, enhancing the ability of FACT to promote reassembly of the nucleosome and/or reinsertion of a deubiquitinated H2A/H2B dimer. Deubiquitination of H2B could potentially favor nucleosome reassembly by enhancing release of FACT from its proposed checkpoint function (McCullough et al., 2018). The sequence of H2B ubiquitination, FACT-mediated nucleosome reorganization, then deubiquitination by Ubp10 and accelerated assembly could propel sequential assembly of nucleosomes, either in the wake of RNA polymerase or during DNA replication. This proposed sequence of events could also occur in humans, as well, given the conservation of all components of this sytem: RAD6B/RNF20/40 are the human E2/E3, USP36 is the homologue of Ubp10 and human FACT, Spt16/SSRP1, is the homologue of the yeast FACT complex, Spt16/Pob3/Nhp6. Our study provides a framework for understanding how H2B-Ub deubiquitination is coupled to the activity of the histone chaperone, FACT, in producing dynamic changes to nucleosome structure, and has exciting implications for understanding the mechanism by which dynamic cycles of ubiquitination and deubiquitination regulate chromatin organization.

Figure 7

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All data generated or analyzed during this study are included in the manuscript and supporting files.

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Author details

1. Melesse Nune

   Program in Molecular Biophysics, Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine, Baltimore, United States

   Contribution

   Conceptualization, Formal analysis, Supervision, Funding acquisition, Investigation, Methodology, Writing—original draft, Project administration, Writing—review and editing

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-3385-3320

2. Michael T Morgan

   Program in Molecular Biophysics, Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine, Baltimore, United States

   Contribution

   Conceptualization, Formal analysis, Supervision, Funding acquisition, Investigation, Methodology, Writing—original draft, Project administration, Writing—review and editing

   Competing interests

   No competing interests declared

3. Zaily Connell

   Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, United States

   Contribution

   Resources, Investigation, Methodology

   Competing interests

   No competing interests declared

4. Laura McCullough

   Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, United States

   Contribution

   Supervision, Investigation, Methodology

   Competing interests

   No competing interests declared

5. Muhammad Jbara

   Schulich Faculty of Chemistry, Technion-Israel Institute of Technology, Haifa, Israel

   Contribution

   Resources, Investigation, Methodology

   Competing interests

   No competing interests declared

6. Hao Sun

   Schulich Faculty of Chemistry, Technion-Israel Institute of Technology, Haifa, Israel

   Contribution

   Investigation, Involved in the synthesis of mercaptolysine amino acid, a critical reagent for semisynthesis of H2Bub

   Competing interests

   No competing interests declared

7. Ashraf Brik

   Schulich Faculty of Chemistry, Technion-Israel Institute of Technology, Haifa, Israel

   Contribution

   Conceptualization, Supervision, Investigation, Methodology, Writing—review and editing

   Competing interests

   No competing interests declared

8. Tim Formosa

   Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, United States

   Contribution

   Conceptualization, Formal analysis, Supervision, Funding acquisition, Investigation, Methodology, Writing—original draft, Project administration, Writing—review and editing

   For correspondence

   tim@biochem.utah.edu

   Competing interests

   Reviewing editor, eLife

   "This ORCID iD identifies the author of this article:" 0000-0002-8477-2483

9. Cynthia Wolberger

   Program in Molecular Biophysics, Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine, Baltimore, United States

   Contribution

   Conceptualization, Formal analysis, Supervision, Funding acquisition, Investigation, Methodology, Writing—original draft, Project administration, Writing—review and editing

   For correspondence

   cwolberg@jhmi.edu

   Competing interests

   Reviewing editor, eLife

   "This ORCID iD identifies the author of this article:" 0000-0001-8578-2969

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