MOZ and MORF, two large MYSTic HATs in normal and cancer stem ...

Oncogene (2007) 26, 5408–5419

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REVIEW

MOZ and MORF, two large MYSTic HATs in normal and cancer stem cells X-J Yang and M Ullah Molecular Oncology Group, Department of Medicine, McGill University Health Center, Montreál, Que´bec, Canada

Genes of the human monocytic leukemia zinc-finger protein MOZ (HUGO symbol, MYST3) and its paralog MORF (MYST4) are rearranged in chromosome translocations associated with acute myeloid leukemia and/or benign uterine leiomyomata. Both proteins have intrinsic histone acetyltransferase activity and are components of quartet complexes with noncatalytic subunits containing the bromodomain, plant homeodomain-linked (PHD) finger and proline-tryptophan-tryptophan-proline (PWWP)-containing domain, three types of structural modules characteristic of chromatin regulators. Although leukemia-derived fusion proteins such as MOZ-TIF2 promote self-renewal of leukemic stem cells, recent studies indicate that murine MOZ and MORF are important for proper development of hematopoietic and neurogenic progenitors, respectively, thereby highlighting the importance of epigenetic integrity in safeguarding stem cell identity. Oncogene (2007) 26, 5408–5419; doi:10.1038/sj.onc.1210609 Keywords: lysine acetylation; MYST acetyltransferase; ING5; BR140; CBP; Runx1

Introduction Like many other human diseases, cancer is a pathological condition with genetic and epigenetic basis (reviewed in Baylin and Herman, 2000; Jaenisch and Bird, 2003; Egger et al., 2004). Although genetic alteration is irreversible, epigenetic changes are sometimes reversible. Diet, lifestyle, social interaction and environmental cues can trigger the reset of epigenetic programs, opening unique windows of opportunity for potential therapeutic intervention (for reviews, see Egger et al., 2004; Wade and Archer, 2006; Nuyt and Szyf, 2007). How nuclear DNA is packaged into chromatin is a major epigenetic determinant. The specific chromatin organization in a given cell type (that is, the packaging state of nuclear DNA) is important for its unique gene expression pattern. A cancer cell may possess an aberrant chromatin organization and thus an abnormal gene expression Correspondence: Dr X-J Yang, Molecular Oncology Group, Royal Victoria Hospital, Room H5.41, McGill University Health Center, 687 Pine Avenue West, Montreál, Que´bec H3A 1A1, Canada. E-mail: [email protected]

pattern. For cancer biology, it is thus important to understand the fundamental mechanisms whereby chromatin structure and function are regulated. In the past two decades, our knowledge about regulation in this field has exploded. Known regulatory mechanisms include chromatin assembly, ATP-dependent remodeling, covalent modification, condensin-mediated condensation, replacement with histone variants, and association of noncoding RNA (reviewed by Horn and Peterson, 2002; Khorasanizadeh, 2004; Li et al., 2007). Covalent modification can occur at both the DNA and histone levels. With histones, modifications include acetylation, phosphorylation, methylation, ubiquitination, and many others (for reviews, see Spencer and Davie, 1999; Strahl and Allis, 2000; Berger, 2002; Jason et al., 2002; Kouzarides, 2007). Different modifications interplay with each other and contribute significantly to the formation of a complex epigenetic program for generating and preserving the defined chromatin state of a given cell type. Within this program, histone acetyltransferases (HATs) play an integral role (reviewed in Sterner and Berger, 2000; Roth et al., 2001; Yang, 2004; Lee and Workman, 2007). As a pair of such enzymes, MOZ (monocytic leukemic zinc-finger protein) and MORF (MOZ-related factor) are important for different developmental programs and have been implicated in leukemogenic and other tumorigenic processes. Here, we start with a brief overview about the discovery of this pair and related acetyltransferases. We then summarize molecular and genetic studies about this pair of HATs and discuss how their multiprotein complexes may act as functional units to process molecular information from histone methylation, phosphoinositides and other signaling cues for acetylation-based action in normal and cancer stem cells.

Identification of MOZ, MORF and other MYSTic HATs The MOZ gene was initially identified as a fusion partner rearranged in the recurrent chromosome translocation t(8;16)(p11;p13) (Borrow et al., 1996). Independently, elegant genetic analysis in budding yeast identified Sas2 (something about silencing 2) and Sas3 as two homologous regulators of gene silencing (Reifsnyder et al., 1996). Sequence comparison revealed

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that the three proteins display high sequence similarity within a B300-residue region with TIP60 (HIV Tatinteractive protein of 60 kDa) (Kamine et al., 1996). The homologous region was named the MYST (MOZ, Ybf2/ Sas3, Sas2 and TIP60) domain (Borrow et al., 1996; Reifsnyder et al., 1996). A putative acetyl-CoA-binding motif within the domain led to the hypothesis that these proteins are HATs. It was the time when the first few HATs were identified, so this hypothesis generated a considerable amount of excitement. The hypothesis received additional support from the discovery that a mutation within the putative acetyl-CoA-binding motif of Drosophila Mof (male-absent on the first), the fifth protein found to have the MYST domain, compromises its crucial role in gene dosage compensation (Hilfiker et al., 1997). TIP60 and yeast Esa1 (essential Sas2related acetyltransferase 1) were then demonstrated to possess intrinsic HAT activity (Yamamoto and Horikoshi, 1997; Smith et al., 1998). HBO1 (HAT bound to ORC1) was identified as a binding partner of ORC1 (replication origin complex 1) (Iizuka and Stillman, 1999). BLAST search against expressed sequence tag databases for additional MYST proteins led to the identification of human MORF as a MOZ paralog (Champagne et al., 1999), and murine MORF was identified independently as Querkopf (Thomas et al., 2000). There are three MYST proteins in budding yeast and five in Drosophila or humans (Figure 1). Notably, the MYST domain is the only structural feature common to all members of this family. Metazoan TIP60 proteins are orthologous to Esa1 owing to similar domain organization, complex formation and cellular function (Doyon and Coˆte´, 2004). At the functional level, metazoan MOF proteins are somewhat similar to Sas2 (Rea et al., 2007). Like TIP60 and MOF, human HBO1 is highly homologous to its counterpart in Drosophila (Hilfiker et al., 1997; Iizuka and Stillman, 1999; Smith et al., 2005; Mendjan et al., 2006). By contrast, MOZ and MORF only show sequence similarity to the very N-terminal region and MYST domain of Enok (Enoki mushroom), the most related Drosophila protein (Figures 1a and b) (Scott et al., 2001; Yang, 2004). Different from Drosophila, zebrafish possesses orthologs of MOZ and MORF (Figure 1c). Thus, different from TIP60, MOF and HBO1, both MOZ and MORF are vertebrate-specific. The MYST family of HATs was not as widely studied as Gcn5/PCAF and p300/CBP, but this situation has changed greatly in the past few years. It is now known that MYST proteins have important roles in various biological processes (Ceol and Horvitz, 2004; Kusch et al., 2004; Dou et al., 2005; Smith et al., 2005; Mendjan et al., 2006; Sykes et al., 2006; Tang et al., 2006). These enzymes have been the subjects of several excellent reviews (Doyon and Coˆte´, 2004; Squatrito et al., 2006; Avvakumov and Coˆte´, 2007; Lafon et al., 2007; Rea et al., 2007; Thomas and Voss, 2007). MOZ and MORF are quite different from other members of this family (Figure 1), so we devote the following sections to this pair of HATs. One thematic line for the sections is how the domain structures of MOZ and MORF determine

their protein complex assembly, biochemical and biological function, and regulation. MOZ and MORF as promiscuous transcriptional co-activators As shown in Figure 1b, MOZ and MORF are highly homologous (overall amino-acid sequence identity, 60%; similarity, 66%), but only show homology to the MYST domains of TIP60, MOF and HBO1. MOZ and MORF are large proteins (B250 kDa) and possess intrinsic HAT activity attributable to their MYST domains (Champagne et al., 1999, 2001; Thomas et al., 2000; Kitabayashi et al., 2001a). Both histones H3 and H4 are the substrates in vitro. Analysis of recombinant MORF proteins, expressed in and affinity-purified from insect cells, indicates that the full-length protein is more active than the MYST domain alone (Champagne et al., 1999; Pelletier et al., 2003), suggesting that the HAT activity is regulated by other domains or association with other proteins. Both MOZ and MORF are autoacetylated (Champagne et al., 1999), with one acetylation site located C terminus to the MYST domain (Kim et al., 2006). But the functional significance of this modification remains to be determined. As shown in Figure 1b, other protein domains of MOZ and MORF include an NEMM (N-terminal part of Enok, MOZ or MORF) domain, tandem PHD (plant homeodomain-linked) zinc fingers, a long acidic stretch, and an SM (serine/methionine-rich) region. The C-terminal part of the NEMM domain shows some sequence similarity to histones H1 and H5, but the function of this domain is not that clear. The H15-like domain was shown to promote nuclear targeting (Kitabayashi et al., 2001a). The tandem PHD fingers are similar to those of Requiem and homologs (Figure 1) (Borrow et al., 1996; Nabirochkina et al., 2002). Requiem is part of an interaction network controlling pluripotency of embryonic stem cells (Wang et al., 2006). These fingers may have important function. One possibility is to recognize methyl-lysine-containing motifs (Kouzarides, 2007). The SM domain possesses transcriptional activation potential, so it was hypothesized that MOZ and MORF are transcriptional coregulators (Champagne et al., 1999, 2001). Indeed, they interact with Runx proteins and activate transcription (Kitabayashi et al., 2001a; Pelletier et al., 2002; Bristow and Shore, 2003; Kindle et al., 2005). Upon association with corepressors such as TLE proteins and histone deacetylases (Levanon et al., 1998; Westendorf et al., 2002; Schroeder et al., 2004; Vega et al., 2004), Runx proteins can function as repressors, raising the interesting question how the antagonizing repressor and activator roles of Runx proteins are regulated. One possibility is that cell signaling controls the switch from one role to the other (Figure 2a). If so, this would be an important mechanism for regulating function of MOZ and MORF. MOZ has been shown to physically and functionally interact with PU.1, an ETS transcription factor that is Oncogene


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Figure 1 Domain organization of MYST proteins from Drosophila (a), humans (b) and the zebrafish Danio rerio (c). For the zebrafish, only MOZ and MORF orthologs (GenBank accession numbers AAT11171 and XP_697383, respectively) are shown. HUGO names for four human proteins are listed in parenthesis. Domains are labeled as follows: Chromo, chromodomain; Ser, serinerich domain; CH, cysteine/histidine-rich motif; NEMM, N-terminal part of Enok, MOZ or MORF; H15, histones H1- and H5-like domain; PHD, plant homeodomain-linked zinc finger; ED, glutamate/aspartate-rich region; and SM, serine/methionine-rich domain. Within the SM domain of MOZ, there is a proline/glutamine-stretch (labeled by the letter P). Numbers at the right correspond to total residues that each protein possesses. Solid lines underneath the MYST and SM domains of MORF denote the HAT and transcriptional activation domains, respectively. The tandem PHD fingers of Enok, MOZ and MORF are highly homolgous to those of Requiem and homologs (identity B40%, similarity B55%), so the domain organization of Drosophila and human Requiem proteins is also shown for comparison.

essential for the development of myeloid and lymphoid lineages (Katsumoto et al., 2006), whereas MORF is present in the transcriptional co-activator complex associated with the nuclear receptor peroxisome proliferator-activated receptor-a (PPARa) (Surapureddi et al., 2002). Studies in mouse and zebrafish indicate MOZ plays a key role in controlling Hox gene expression (Miller et al., 2004; Camos et al., 2006; Crump et al., 2006; Katsumoto et al., 2006), so unknown DNA-binding transcription factors may recruit MOZ to achieve this goal. In addition, MOZ functions as a co-activator of the Nrf2MafK heterodimer to upregulate the expression of Oncogene

GSTP (glutathione S-transferase placental form), a detoxification enzyme, during hepatocarcinogenesis (Ohta et al., 2007). Both MOZ and MORF are widely expressed in various mouse and human tissues (Borrow et al., 1996; Champagne et al., 1999; Thomas et al., 2000, 2006; Katsumoto et al., 2006), so similar to GCN5/PCAF and p300/CBP, they may function as co-activators for many transcription factors. This interesting possibility awaits further investigation. As discussed below, MOZ and MORF are part of tetrameric complexes and noncatalytic subunits modulate the roles of these two transcriptional co-activators.


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Figure 2 MOZ and MORF acetyltransferases as molecular processing units. (a) Runx proteins recruit transcriptional corepressors such as histone deacetylases (HDACs) and TLE proteins for transcriptional repression. Upon stimulation by specific signaling events, these corepressors dissociate and co-activators such as MOZ/MORF acetyltransferase complexes associate with Runx proteins to activate transcription. The signaling events involved remain to be determined. (b) Domain organization of proteins associated with MOZ and MORF. LZ, leucine zipper; ING, ING N-terminal domain; BN, BRPF N-terminal region; I and M, the N-terminal and C-terminal parts of the Epc-homology region, respectively; bromo, bromodomain; PWWP, proline-tryptophan-tryptophan-prolinecontaining domain; and OM, octapeptide motif. dBRPF is derived from NP_610266, and BRPF1 is also known as BR140 (Thompson et al., 1994). (c) MOZ and MORF complexes act as ‘molecular processing units’ to carry out targeted acetylation of histone H3 in response to signaling cues from other chromatin modifiers (for example, histone methyltransferases) and cellular signaling events (for example, phosphoinositides). This modification is part of an integrated epigenetic program important for defining chromatin organization and determining specific gene expression patterns. Question marks denote links awaiting further investigation.

MOZ and MORF as catalytic subunits of quartet complexes Like HAT1, Gcn5, PCAF and many other HATs (Doyon and Coˆte´, 2004; Lee and Workman, 2007; Nagy and Tora, 2007; Parthun, 2007), MOZ and MORF are catalytic components of protein complexes. They were recently found to be stoichiometric subunits of ING5 (inhibitor of growth 5) complexes (Doyon et al., 2006). Other subunits of the complexes are EAF6 (homolog of Esa1-associated factor 6) and BRPF1/2/3 (bromodomain-PHD finger protein 1, 2

or 3) (Figure 2b). Different from MOZ and MORF alone (Champagne et al., 1999; Kitabayashi et al., 2001a), ING5-MOZ/MORF complexes acetylate only histone H3 at lysine 14 (Doyon et al., 2006). Consistent with this, at least BRPF1 stimulates the transcriptional co-activator and HAT activities of MOZ (M Ullah, J Coˆte´ and XJ Yang, unpublished data), further suggesting that noncatalytic subunits affect the function of MOZ and MORF. As its name implies, yeast Eaf6 was initially identified as a subunit of the Esa1 complex NuA4 (Doyon and Coˆte´, 2004). The only recognizable domain in EAF6 is a Oncogene


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leucine zipper, located at the N-terminal part. The three BRPF proteins are highly homologous and contain multiple domains (Figure 2b). Each BRPF possesses a bromodomain and a proline-tryptophan-tryptophanproline-containing (PWWP) domain, with the former having the potential to recognize acetyl-lysine motifs (Seet et al., 2006). The PWWP domain is a 100- to 150residue module with a highly conserved proline-tryptophan-tryptophan-proline motif and has been proposed to have methyl-lysine-binding ability (Stec et al., 2000; Maurer-Stroh et al., 2003). Domains I and M of BRPFs are similar to the N-terminal region of Epc1/2 (enhancer of polycomb 1 or 2), a subunit of the TIP60 complex (Figure 2b) (Doyon et al., 2006). These two small domains are homologous to an N-terminal region of Drosophila Epc and have been collectively referred to as Epc-N (Figure 2b) (Perry, 2006). Different from those in Epc1/2, domains I and M of BRPFs are separated by a cluster of zinc fingers, referred to as PZPM (PHD/Zn-knuckle/PHD motif), containing two PHD fingers linked by a mononuclear zinc knuckle. PZPM domains are also present in AF10 and AF17 (Figure 2b), two frequent fusion partners in MLL-associated leukemia, as well as in a Jumonjidomain histone demethylase and the NSD family of histone methyltransferases (Perry, 2006). Thus, such domains may be important for chromatin regulation. Unexpected from the limited sequence similarity of Enok to MOZ and MORF, one authentic BRPF ortholog is present in Drosophila (Figure 2b). Moreover, the Caenorhabditis elegans protein Lin49 is highly homologous to BRPFs except for its PWWP domain (Figure 2b) (Chamberlin and Thomas, 2000). Thus, it is likely that the physical link of BRPF proteins to MOZ and MORF was acquired late during revolution. ING5 is also a stoichiometric subunit of HBO1 complexes, which contain EAF6 and Jade1/2/3 (gene for apoptosis and differentiation in epithelia 1, -2 or -3) (Doyon et al., 2006). The Jade proteins are highly homologous and share the Epc-N and PZPM domains with BRPF proteins (Figure 2b), so these HBO1 complexes are very similar to MOZ/MORF complexes. Consistent with its high sequence similarity to ING5, ING4 also forms tetrameric complexes with HBO1, EAF6 and Jade proteins. However, ING4 does not appear to form complexes with MOZ and MORF under physiological conditions. ING4 and ING5 are two members of the ING family of putative tumor suppressors (Gong et al., 2005). There are five known members in humans. According to their sequence similarity, ING proteins can be divided into three subgroups: ING4 and ING5; ING1 and ING2; and ING3. Both ING1 and ING2 are components of Sin3-HDAC complexes (Loewith et al., 2001; Kuzmichev et al., 2002; Doyon et al., 2006), whereas ING3 is a subunit of TIP60 complexes (Loewith et al., 2000; Doyon et al., 2004; Gong et al., 2005). It is worth to note that a tetrameric TIP60 complex core, containing EAF6 and Epc1/2, is very similar to ING4 and ING5 complexes (Doyon and Coˆte´, 2004). Thus, ING3, -4 and -5 complexes share quartet architecture: a MYST Oncogene

HAT, an ING, EAF6 and an Epc-N domain protein. Strikingly, such architecture is conserved in yeast NuA3 and piccolo NuA4 complexes, which have the subunit compositions Sas3-Yng1-Eaf6-Not1 and Esa1-Yng2Eaf6-Epl1 (Epc-like 1), respectively (Carrozza et al., 2003; Doyon and Coˆte´, 2004). Yng1 and Yng2 are two yeast ING proteins. Within NuA4, Epl1 serves as a scaffold protein bridging Yng2, Eaf6 and Esa1 to form the acetyltransferase core (Boudreault et al., 2003). Similarly, Epc1/2 bridges the interaction of TIP60 with ING3 and EAF6 to form the tetrameric acetyltransferase core (Doyon et al., 2004), so an interesting possibility is whether BRPFs play a similar role in assembling and modulating MOZ and MORF complexes (Doyon et al., 2006). Biochemical characterization revealed that BRPF1 serves as a scaffold bridging the association of MOZ and MORF with ING5 and Eaf6 (Figure 2c) (M Ullah, J Coˆte´ and XJ Yang, unpublished data), attesting that these complexes resemble those of HBO1 and the core complex of TIP60 (Doyon et al., 2006). These four HATs show sequence similarity only in the MYST domain (Figure 1b), so this domain may be key to complex formation. Indeed, the MYST domains of MOZ and MORF mediate the interaction with BRPF1, ING5 and EAF6 (M Ullah, J Coˆte´ and XJ Yang, unpublished data). As shown in Figure 2b, ING5 has a PHD finger, whose sequence is quite different from those of MOZ, MORF and BRPFs. PHD fingers are present in many chromatin regulators (Saha et al., 1995). As PHD fingers have the potential to bind phosphoinositides and are implicated in nuclear lipid signaling (Gozani et al., 2003), an interesting possibility is that phosphoinositides bind directly to MOZ and MORF complexes and regulate their activity. PHD fingers may also function as methyl-lysine-binding modules. One PHD finger of NURF recognizes trimethyl lysine 4 of histone H3 to couple ATP-dependent chromatin remodeling to histone methylation (Li et al., 2006; Wysocka et al., 2006), and the PHD finger of ING2 binds to the same mark to stimulate methylation-dependent deacetylation (Pena et al., 2006; Shi et al., 2006). Moreover, methylation of histone H3 at lysine 4 promotes association with yeast Yng1, a subunit of the NuA3 acetyltransferase complex (Martin et al., 2006; Taverna et al., 2006). Like ING2, ING5 binds to trimethyl lysine 4 of histone H3 through its PHD domain (Shi et al., 2006), raising the interesting possibility that ING5 facilitates methylation-dependent histone acetylation by MOZ or MORF. As there are four additional PHD fingers within a MOZ or MORF complex (Figures 1 and 2b), PHD fingers may recognize different histone methylation states and act as protein modules to process molecular information from histone methylation marks for modulation of HAT activity (Figure 2c). Phosphoinositides may also regulate methyl-lysine-binding ability to modulate the acetyltransferase activity of MOZ and MORF complexes (Figure 2c). Based on different domains that they possess, it is tempting to propose that MOZ and MORF complexes process and convert molecular information


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from other chromatin modifiers, as well as from cellular signaling networks (Figure 2c), for acetylation-based action in different developmental processes. MOZ and MORF in mouse and zebrafish development Initial evidence about the role of MORF in mouse development came from elegant analysis of a hypomorphic allele known as Querkopf (Thomas et al., 2000). With a residual MORF mRNA level of B10%, homozygous mice are small in size and display craniofacial abnormalities and severe defects in cerebral cortex development, suggesting that MORF is important for neurogenesis. Neural progenitor cells from these mice exhibit defects in self-renewal and differentiation (Merson et al., 2006). Related to this, Enok is required for mushroom body formation in fly brain (Scott et al., 2001). Moreover, the BRPF ortholog Lin49 in C. elegans (Figure 2b) is part of a transcriptional hierarchy important for the control of left/right asymmetry in chemosensory neurons (Chamberlin and Thomas, 2000; Chang et al., 2003). The craniofacial abnormalities of Querkopf mice are in part due to defects in calvarial bones (Thomas et al., 2000). Consistent with this, MORF is able to interact physically and functionally with Runx2, a Runt-domain transcription factor with high homology to Drosophila Runt and a key player in osteoblast differentiation (Pelletier et al., 2002), suggesting that MORF may play a role in regulating gene expression during osteogenesis. Murine MOZ is widely expressed during embryonic development and in adult tissues (Borrow et al., 1996; Katsumoto et al., 2006; Thomas et al., 2006). Two research groups mutated the gene by homologous recombination. One group introduced an insertion mutation, resulting in truncation of the MOZ protein at residue 1538 and deletion of the SM domain (Figure 1b) (Thomas et al., 2006). The mRNA level is normal, but the mutant protein is undetectable perhaps due to instability and/or insufficient translation. Homozygous mice die at birth, with reduced hematopoiesis and profound defects in the stem cell compartment. These mice have no long-term repopulating stem cells and display substantial reduction in the number of multipotent cells able to form spleen colonies. The other research group replaced exon 2 (containing the first translation codon) with a neo gene cassette (Katsumoto et al., 2006). Although heterozygotes are fertile and exhibit no obvious morphological defects, homozygous mutation is embryonic lethal. Homozygous embryos remain alive until E14.5, and no truncated protein or mRNA is detectable. There are fewer hematopoietic stem progenitor cells in fetal livers. Moreover, expression of c-kit, c-Mpl and HoxA9 is reduced. HoxA9 is a key player in hematopoiesis and leukemogenesis (Grier et al., 2005), and its nuclear localization is promoted by thrombopietin, the ligand of c-Mpl (Kirito et al., 2004). Moreover, there is a genetic interaction between c-kit and c-Mpl in repopulating hematopoietic stem cells (Antonchuk et al., 2004). Thus, MOZ regulates

expression of genes required for proliferation and repopulation of potential of stem cells in the hematopoietic compartment. Consistent with this, MOZ interacts with Runx1 and PU.1, two important hematopoietic transcription factors (Kitabayashi et al., 2001a; Pelletier et al., 2002; Katsumoto et al., 2006). Through Runx1, MOZ regulates the expression of MIP-1a, a proinflammatory factor that controls proliferation of hematopietic progenitors (Bristow and Shore, 2003). Furthermore, MOZ expression is under direct control of Nanog, Oct4 and Sox2 in embryonic stem cells (Boyer et al., 2005). Therefore, emerging evidence suggests that MOZ and MORF play important roles in different stem cell compartments (Figures 3 and 4). While little is known about zMORF in zebrafish (Figure 1c), function of zMOZ has been analysed recently. Transformation of the second pharyngeal arch into a mirror-image duplicated jaw was observed in two mutant zebrafish lines containing translational stop codons for the acidic region of zMOZ (Miller et al., 2004). These mutations are expected to produce truncated proteins with intact NEMM and MYST domains (Figure 2b), although it is unclear whether these proteins are stable in vivo. The zebrafish mutants also display defects in the third and fourth pharyngeal arches and in facial motor neuron migration. Analysis of these mutants revealed that zMOZ is important for maintaining Hox expression in the hindbrain and postmigratory cranial neural crest, but not for earlier Hox expression at premigratory stages (Miller et al., 2004; Crump et al., 2006). zMOZ-dependent expression of Hox proteins such as Hoxa2a and Hoxa2b controls segment-specific fate maps of facial skeletal precursors. Related to this, Hoxa2 is important for development of mouse facial somatosensory map (Oury et al., 2006) and Lin49 controls Hox-C expression in C. elegans (Chamberlin and Thomas, 2000; Chang et al., 2003). All of these suggest that zMOZ is important for skeletogenesis in zebrafish. Taken together, studies of MOZ and MORF in mice and zebrafish suggest that these two paralogous HATs are not functionally redundant in vertebrate development. MOZ and MORF in leukemia, leiomyomata and other malignancies Consistent with its important role in hematopoiesis, the MOZ gene is rearranged in chromosome translocations associated with acute myeloid leukemia (AML) or therapyrelated myelodysplastic syndromes. The balanced chromosome translocation t(8;16)(p11;p13) is found in o1% of AML patients, especially prominent in French– American–British M4/M5 subtypes. The patients are characterized by a block in blast differentiation at the granulo-monocytic stage and associated with a poor response to chemotherapy. In this recurrent translocation, the MOZ gene on chromosome 8p11 is fused to the CBP gene on 16p13, producing a transcript encoding the fusion protein MOZ-CBP (Figure 3a) (Borrow et al., 1996). The reverse fusion transcript is out of frame and Oncogene


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Figure 3 Schematic representation of leukemic fusion proteins from representative chromosome translocations. The domain structure of MOZ is as shown in Figure 1b, with breakpoints marked by vertical arrows. Domains for CBP (a) and TIF2 (b) are labeled as follows: KIX, phospho-CREB-interacting module; Br, bromodomain; Q, glutamine-rich domain; bHLH, basic helix–loop–helix; PAS, Per, aryl hydrocarbon receptor (AhR) and single-minded homology; NID, nuclear receptor-interacting domain; and CID, CBP/p300interacting domain. While MOZ-CBP possesses double HAT domains and is a ‘super-HAT’ (a), MOZ-TIF2 associates with CBP (or p300) and forms a ‘super-HAT’ complex for aberrant acetylation (b). How the fusion proteins generate aberrant acetylation patterns in vivo is an important issue that remains to be addressed.

produces no protein. MOZ-CBP lacks the SM domain of MOZ, but gains almost all of CBP (Figure 3a). Mirroring the homology between p300 and CBP, the MOZ gene is fused to that of p300 in translocation t(8;22)(p11;q13) (Chaffanet et al., 2000; Kitabayashi et al., 2001b). Moreover, in t(10;16)(q22;p13) associated with childhood AML or therapeutic myelodysplastic syndromes, the MORF gene on 10q22 (Champagne et al., 1999) is fused to that of CBP (Panagopoulos et al., 2001; Kojima et al., 2003). MOZ-p300 and MORFCBP show similar domain organization to MOZ-CBP (Figure 3a). In addition to leukemia and myelodysplastic syndromes, the MORF gene is disrupted in multiple cases of uterine leiomyomata with t(10;17)(p11;q21) (Moore et al., 2004). The fusion partner on 17q21 remains to be identified, but an attractive candidate is GCN5. Thus, like the translocations described above, two HATs may be involved in this chromosomal abnormality, thereby causing aberrant histone acetylation and abnormal gene expression (Figure 4). Consistent with this, gene expression profiling of samples from AML patients with t(8;16)(p11;p13) revealed a characteristic Oncogene

pattern of Hox gene expression, with elevated levels of HOXA9, HOXA10 and MEIS1 (Camos et al., 2006). Increased expression of these proteins has been linked to leukemia induction (Grier et al., 2005). TIF2 (transcription intermediary factor 2) is a third fusion partner identified for MOZ. In the chromosome inversion inv(8)(p11;q13) associated with AML or mixed lineage leukemia, the MOZ gene is fused to that of TIF2 on 8q13 (Carapeti et al., 1998; Liang et al., 1998). TIF2 is a member of the p160 family of nuclear receptor co-activators known to interact with p300 and CBP (Leo and Chen, 2000). The CBP/p300-interacting domain (CID) of TIF2 remains intact in MOZ-TIF2 resulting from inv(8)(p11;q13), suggesting that this fusion protein acts through p300 and CBP and that aberrant acetylation plays a role in leukemogenesis (Figure 3b). MOZ-TIF2 displays intrinsic transforming ability in vitro and induces AML in murine bone marrow transplant assays (Deguchi et al., 2003). In support of the involvement of p300 and CBP, the CID of TIF2 is crucial for these activities. Unlike BCRABL, MOZ-TIF2 confers self-renewal properties to committed murine hematopoietic progenitors and its


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a

b

ING5 EAF6 BRPF

ING5 EAF6 BRPF

MOZ/MORF

Normal epigenetic programs

MOZ

Hematopoietic

MOZ/MORF-X

Oncogenic epigenetic programs

MORF

MOZ or MORF

Neural

Other?

MOZ-CBP? MOZ-p300? MORF-CBP? MOZ-TIF2

Leukemic

MORF-GCN5??

Aberrant MOZ or MORF

Leiomyoma

Other cancer?

Type of stem cells

Figure 4 Schematic illustration of roles of MOZ and MORF in normal and cancer stem cells. (a) Tetrameric MOZ or MORF complexes are proposed to carry out histone H3 acetylation for generating and maintaining proper epigenetic programs in hematopoietic, neural and other stem cells. MOZ and MORF have been shown to be important for proper development of hematopoietic and neural progenitors, respectively, but it is unclear whether they also function in other stem cell compartments. (b) Chromosome translocations lead to the production of fusion proteins such as MOZ-CBP, MOZ-p300, MORF-CBP and MOZTIF2 (collectively referred to as MOZ/MORF-X), which possess intact MYST domains for tetrameric complex formation. These abnormal HAT complexes alter normal epigenetic programs and change chromatin organization and gene expression patterns. Among the fusion proteins, only MOZ-TIF2 has been shown to promote self-renewal of leukemic stem cells, so additional studies are needed to determine whether other fusion proteins can also do so. It remains to be determined whether GCN5 is involved in leiomyomata with t(10;17); different from other known chromosome abnormalities involving MOZ or MORF, the MYST domain is disrupted in this translocation (Moore et al., 2004). Needless to say, additional investigation is needed to establish whether MOZ and MORF play a role in other types of cancer.

expression results in AML that can be serially transplanted, so MOZ-TIF2 is a unique leukemic gene product (Huntly et al., 2004). At the molecular level, MOZ-TIF2 depletes CBP from PML bodies to inhibit transcriptional activity of p53 and the retinoic acid receptor RAR (Kindle et al., 2005; Collins et al., 2006). Through p300 or CBP, MOZ-TIF2 may deregulate chromatin acetylation. Thus, leukemic MOZ and MORF fusion proteins have the potential to induce aberrant epigenetic alterations (Figure 3). The MYST domain is intact in most of the fusion proteins (Figure 3) and sufficient for mediating tetrameric complex formation (M Ullah, J Coˆte´ and XJ Yang, unpublished data), so the leukemic fusion proteins may form tetrameric complexes with ING5, EAF6 and a BRPF protein, resulting in aberrant acetylation (Figure 4). One interesting question is whether MOZ and MORF also affect other malignancies. It has been suggested that both play a role in maintaining acetylation of histone H4 at lysine 16, a hallmark of cancer (Fraga et al., 2005). Moreover, the RUNX1 gene is frequently involved in human acute leukemia, RUNX2 has oncogenic potential, and Runx3 expression is frequently silenced in different types of cancer (reviewed by Ito, 2004). Leukemia-associated Runx1 proteins often lack the C-terminal domain, a region important for association with MOZ and MORF. Reduced expression of Runx3 may affect its normal partnership with MOZ and MORF. It is also possible that in addition to chromosome translocation and inversion, other abnormalities such as small deletion, point mutation, and deregulated

expression of MOZ and MORF may also cause malignancies. MOZ and MORF are catalytic subunits of quartet complexes (Doyon et al., 2006), so it is tempting to speculate that genes of the associated subunits may be mutated in cancers. In addition to genetic abnormalities in AML, therapy-related myelodysplastic syndromes, and leiomyomata, function of MOZ and MORF may be impaired in other types of cancer (Figure 4). Notably, future investigation is needed to examine interesting possibilities. Conclusions and perspectives Mammalian GCN5/PCAF and p300/CBP are two pairs of HATs well known to have important roles in diverse cellular processes (reviewed in Goodman and Smolik, 2000; Sterner and Berger, 2000; Roth et al., 2001; Lee and Workman, 2007). MOZ and MORF constitute a third pair (Figure 1). Like GCN5/PCAF and p300/CBP, MOZ and MORF are transcriptional co-activators with intrinsic HAT activity. In their quartet complexes, noncatalytic subunits such as BRPF proteins modulate HAT activity and co-activator potential of MOZ and MORF (Doyon et al., 2006). GCN5/PCAF and p300/ CBP also acetylate many non-histone proteins (for a recent review, see Yang and Gre´goire, 2007), so it will be interesting to determine whether MOZ and MORF are able to do so. It will also be interesting to investigate whether they act through ING5 to regulate activities of p53 and nuclear factor-kB, which are known to bind Oncogene


5416

ING proteins (Gong et al., 2005). MOZ is important for expression of Hox proteins, so one possible mechanism is that DNA-binding transcription factors recruit MOZ to the Hox gene promoters. Thus, MOZ and MORF may function as co-activators for multiple transcription factors. In addition, they may have a role in other nuclear processes such as DNA replication (Doyon et al., 2006). Different epigenetic regulators interplay with each other to form an integrated epigenetic program for coordinated regulation, so an important question is how MOZ and MORF may interact with other epigenetic regulators. Within one MOZ or MORF complex (Doyon et al., 2006), there are one bromodomain, five PHD fingers and one PWWP domain (Figures 1b and 2), which have the potential to recognize acetyl or methyl histones, thereby leading to crosstalk with other chromatin modifiers and regulators. PHD fingers may also recognize phosphoinositides. Moreover, cellular signaling networks may directly modify MOZ and MORF complexes to regulate their activities. Thus, it will be interesting and also important to determine how these complexes process and integrate molecular information from other epigenetic regulators and cellular signaling networks (Figure 2c). MOZ and MORF play a key role in regulating different developmental programs, including skeletogenesis, neurogenesis and hematopoiesis. Although MOZ

regulates hematopoiesis and proliferation of related progenitor cells (Katsumoto et al., 2006; Thomas et al., 2006), MORF has a key role in the neural stem cell compartment (Merson et al., 2006), raising an interesting possibility as to whether MOZ and MORF play a role in other stem cells during normal development (Figure 4a). The leukemic fusion protein MOZ-TIF2 has been shown to promote self-renewal of leukemic stem cells (Huntly et al., 2004), so one question is whether other leukemia-derived MOZ and MORF proteins have a similar role (Figure 4b). These aberrant proteins may be valuable molecular targets of cancer ‘epigenetic therapy,’ so their molecular and functional analysis will also help develop novel therapeutics. In conclusion, MOZ and MORF have just emerged as a novel pair of HATs important for regulating chromatin dynamics, preserving epigenetic integrity, and safeguarding stem cell identity in human and other vertebrates. Acknowledgements We thank Jacques Coˆte´ for sharing unpublished results about MYST protein complexes and two anonymous reviewers for constructive comments on a previous version of this paper. Related research was supported by funds from the National Cancer Institute of Canada and the Canadian Institutes for Health Research (to XJY).

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