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Department of Biology, Syracuse University, Syracuse, New York 13244
1 Corresponding author: Department of Biology, Syracuse University, 130 College Pl., BRL 703, Syracuse, NY 13244.
E-mail: bcalvi{at}syr.edu
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ABSTRACT |
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 TOP ABSTRACT MATERIALS AND METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSLITERATURE CITED |
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40 million years of evolution and provide evidence that additional gene loci may be amplified in some species. Further, we find that the acetylation of nucleosomes and Orc2 protein binding at active amplification origins is conserved. Conservation of DNA subsequences within amplification origins from the 12 recently sequenced Drosophila species genomes implicates members of a Myb protein complex in recruiting acetylases to the origin. Our findings suggest that conserved developmental mechanisms integrate egg chamber morphogenesis with cell cycle modifications and the epigenetic regulation of origins.
Oogenesis in Drosophila melanogaster is a model genetic system for understanding how cell cycle programs and origin regulation are modified in coordination with development (SPRADLING 1993; LILLY and DURONIO 2005; SWANHART et al. 2005 for reviews). The cell cycles of both germline and somatic cells are precisely coordinated with the maturation of the egg chamber as it migrates down an ovariole (Figure 1, A and B). Both the germline and somatic cell precursors originate from stem cells in the germarium at the anterior tip of the ovariole and initially divide by a mitotic cell cycle (LIN and SPRADLING 1993; MARGOLIS and SPRADLING 1995). Germline cells divide synchronously four times with incomplete cytokinesis resulting in 16 interconnected cells. One of these cells becomes an oocyte and enters meiosis, while its 15 sister cells adopt the nurse cell fate and enter an endocycle (DE CUEVAS et al. 1997; HUYNH and ST JOHNSTON 2004 for reviews). Through repeated endocycles, nurse cells ultimately become highly polyploid by the end of oogenesis (PAINTER and REINDORP 1939; LILLY and SPRADLING 1996; DEJ and SPRADLING 1999). Somatic follicle cells proliferate and then surround the 16-cell germline cyst as it buds off from the germarium, forming a stage 1 egg chamber. While nurse cells have entered the endocycle by this point, the follicle cells continue to mitotically proliferate until stage 6, after which they too enter an endocycle (Figure 1B) (MAHOWALD et al. 1979). The developmental timing of this follicle cell mitotic-to-endocycle transition at stage 6 is coordinated by the Notch signaling pathway (DENG et al. 2001; LOPEZ-SCHIER and ST JOHNSTON 2001; SHCHERBATA et al. 2004). Follicle cells then complete three endocycles from stage 7 to stage 10A, achieving a final ploidy value of 16C (LILLY and SPRADLING 1996; CALVI et al. 1998).
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Genetic and molecular analyses have indicated that the regulation of amplification origins resembles that of other origins in that they are controlled by cell cycle kinases and are licensed by the binding of a pre-replicative complex (pre-RC) (LANDIS et al. 1997; CALVI et al. 1998; ASANO and WHARTON 1999; AUSTIN et al. 1999; LANDIS and TOWER 1999; ROYZMAN et al. 1999; LOEBEL et al. 2000; YAMAMOTO et al. 2000; SCHWED et al. 2002). For many of these proteins, their specific localization to amplification origins and forks can be visualized by immunofluorescent microscopy, for example, the pre-RC protein Orc2 (ROYZMAN et al. 1999). The analysis of amplification has also led to the discovery of new proteins and mechanisms that control origins. For example, a large complex called Myb–MuvB binds to the amplification origins and is essential for their activity. This complex contains the fly orthologs of the human Myb proto-oncogene, Rb tumor-suppressor proteins, and other proteins (BOSCO et al. 2001; BEALL et al. 2002, 2004; KORENJAK et al. 2004; LEWIS et al. 2004).
Analysis of amplification origins, and other origins, have identified cis sequences important for origin function, but a DNA consensus sequence for origins of DNA replication in multicellular eukaryotes has not been identified (ALADJEM et al. 2006 for review). Emerging evidence from a variety of organisms suggests that epigenetic modification plays a major role in origin activity. The modification of chromatin can alter the time when origins initiate replication during S phase and which origins initiate replication in different cells in development (MECHALI 2001; VOGELAUER et al. 2002; LIN et al. 2003; DANIS et al. 2004). In D. melanogaster, the nucleosomes at active amplification origins are hyper-acetylated, suggesting that epigenetic regulation contributes to the differential activity of origins in stage 10B follicle cells (AGGARWAL and CALVI 2004; HARTL et al. 2007). It is not known, however, which histone acetyl transferase enzyme is responsible for this acetylation, nor how this enzyme is recruited specifically to the amplification origins.
It has been previously shown that follicle cells become polyploid and chorion genes amplify in ovaries of several Drosophila species and the Mediterranean fruit fly Cerratitis capitata (MARTINEZ-CRUZADO et al. 1988; SWIMMER et al. 1990; VLACHOU et al. 1997; VLACHOU and KOMITOPOULOU 2001). Here we evaluate the importance of cell cycle developmental timing and the epigenetic regulation of origins by determining whether these processes have been conserved in evolution. We find that the developmental timing, epigenetic regulation, and Orc2 protein binding have been strictly conserved over 40 million years of evolution. We also present evidence that additional loci may be amplified in some species. Conservation of DNA subsequences in the chorion origin among 12 Drosophila species suggests that a Myb complex may recruit acetylases to the origin. Our evidence suggests that the timing of endocycles and amplification are important for oogenesis and that epigenetic regulation is a conserved mechanism that contributes to the developmental specificity of amplification origins.
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MATERIALS AND METHODS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSLITERATURE CITED |
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Ovary antibody labeling and analysis:
Dissection of ovaries, antibody labeling, and confocal analysis were as previously described (CALVI et al. 1998; AGGARWAL and CALVI 2004; CALVI and LILLY 2004). Antibodies and dilutions used were rabbit antiphospho-histone H3 1:500 (Upstate), mouse monoclonal anti-BrdU 1:20 (Becton Dickinson), rabbit polyclonal anti-acetylated histone H3 1:200 (Upstate), rabbit polyclonal anti-acetylated lysine 8 histone H4 1:200 (Upstate), and rabbit polyclonal anti-Orc2 antibody 1:200 (provided by M. Botchan).
Sequence analysis:
Sequence analysis of the third chorion origin began by identifying the orthologs of D. melanogaster chorion protein genes in other species by tblastn of genomic scaffolds from the Consortium for Assembly, Alignment, and Annotation (AAA) of 12 Drosophila genomes (http://rana.lbl.gov/drosophila/) using the FlyBase species blast server (http://flybase.bio.indiana.edu/blast/). Genomic sequence surrounding the cp18 orthologs was then downloaded from the Gbrowse web server (http://flybase.bio.indiana.edu/cgi-bin/gbrowse/dmel/), and subregions were aligned using ClustalW. Regions conserved among chorion loci in Drosophila species were also identified by a blastn search of genomic scaffolds.
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RESULTS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSLITERATURE CITED |
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Conserved developmental timing and cell cycle synchronization of the amplification phase:
Subsequent to endocycles in D. melanogaster, the amplification of select loci can be detected by BrdU incorporation, which appears as four distinct foci of different intensities in follicle cell nuclei beginning in stage 10B of oogenesis (Figures 3B and 4A) (CALVI et al. 1998). Because the homologous polytene chromosomes are paired in follicle cells, each amplified locus is represented by a single focus of BrdU; the large- and medium-size focus corresponding to the highly amplified chorion genes on the third and X chromosome, respectively, while the two smaller foci represent the amplicons at cytogenetic positions 30B and 62D, which amplify to lower levels (Figure 4A) (CALVI et al. 1998; CLAYCOMB et al. 2004). Although the mitotic cycles and endocycles are not synchronized among follicles cells in an egg chamber, the onset of the amplification phase occurs synchronously, which is revealed by the simultaneous appearance of focal BrdU incorporation in all follicle cells around the oocyte in stage 10B (CALVI et al. 1998).
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A high-magnification analysis of the amplification foci revealed a further similarity with D. melanogaster in that they were of different sizes, typically one large, one medium, and two or more small foci (Figure 4, Table 1, and data not shown). It was previously shown that the orthologs of the D. melanogaster chorion genes on the X and third chromosome amplify in D. subobscura, D. virilis, and D. grimshawi. Therefore, the large- and medium-size foci seen in these and other species likely correspond to the highly amplified orthologs of the D. melanogaster chorion genes. The appearance of smaller foci suggests that orthologs of D. melanogaster genes at 30B and 62D may also amplify in these species (Figure 4, B–F, and Table 1). In some species, a greater number of medium- to small-size foci were seen (Table 1). The most extreme example was D. willistoni, which had up to eight foci ranging from large to small sizes (Figure 4F). This suggests that additional, unknown gene loci may amplify in some species.
Acetylation of origin nucleosomes and Orc2 localization is conserved:
The nucleosomes at active amplification origins in D. melanogaster are hyper-acetylated relative to other genomic regions, which in part explains why they are active while other origins in the same nucleus are not (AGGARWAL and CALVI 2004; HARTL et al. 2007). To determine if this epigenetic regulation of amplification origins is conserved, we labeled ovaries from the other species with antibodies raised against poly-acetylated histone H3 (anti-AcH3) and histone H4 acetylated on lysine 8 (anti-H4K8). In all species, these antibodies labeled both germline and somatic cell nuclei in all stages of oogenesis. Beginning in stage 10B, however, one or more prominent foci could be seen in the nuclei of follicle cells surrounding the oocyte, but not in the follicle cells associated with the nurse cells (Figure 5, A–F, and data not shown). Reminiscent of the BrdU foci, the sizes of these acetylation foci differed, although the efficacy of labeling and the number of foci detected differed among samples and species. The spatial and temporal restriction of acetylation foci to follicle cells around the oocyte beginning in stage 10B suggests that they represent amplifying loci.
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Conservation of DNA subsequences at the origin implicates the Myb–MuvB complex in epigenetic regulation:
The evolutionary conservation of nucleosome hyper-acetylation supports previous findings that it plays an important role in origin regulation. It is not known, however, which acetylase is responsible for modifying origin nucleosomes or which proteins recruit this acetylase to the origins. To achieve locus specificity, the proteins responsible for recruiting the acetylase likely bind to DNA sites within origin regions that are essential for origin function. Previous analysis had revealed similarity between amplification origins in D. melanogaster and several other flies (SWIMMER et al. 1990; VLACHOU and KOMITOPOULOU 2001). However, with the recent availability of genome sequences for 12 Drosophila species, we felt that a new bioinformatics analysis was warranted.
We focused on the origin at the third chromosome chorion locus because it is the best defined genetically and molecularly. At this locus, the two most important regions are the 320-bp ACE3 and the 840-bp Ori-β, which are upstream and downstream of the chorion protein 18 (cp18) gene transcription unit, respectively (Figure 7A) (ORR-WEAVER and SPRADLING 1986; DELIDAKIS and KAFATOS 1987, 1989; AUSTIN et al. 1999). Although most replication initiates in Ori-β, both ACE3 and Ori-β are required for high-level amplification, are hyper-acetylated, and are bound by the ORC (DELIDAKIS and KAFATOS 1989; ORR-WEAVER et al. 1989; HECK and SPRADLING 1990; AUSTIN et al. 1999; LU et al. 2001; AGGARWAL and CALVI 2004; HARTL et al. 2007).
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DISCUSSION |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSLITERATURE CITED |
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Conserved developmental timing of cell cycle programs:
In all species that we examined, follicle cells completed mitotic divisions and entered endocycles in mid-oogenesis before stage 7. In D. melanogaster, this transition is controlled by the Notch-signaling pathway, which has several targets for preventing mitosis and promoting endocycles (DENG et al. 2001; LOPEZ-SCHIER and ST JOHNSTON 2001; SHCHERBATA et al. 2004). Our results predict that Notch pathway orthologs also control the timing of endocycle entry in these other species.
The strict conservation of timing for endocycle entry suggests that it is important for egg chamber maturation. One purpose may be to increase the biosynthetic capability of the follicle cells. In addition to their role in developmental patterning and eggshell production, follicle cells also supply yolk and other proteins to the oocyte. The onset of endocycles in stage 7 corresponds to the beginning of vitellogenesis when the oocyte begins to accumulate yolk in earnest. Perhaps more importantly, follicle cell growth in the absence of mitotic division may be more conducive to egg chamber morphogenesis. From stage 6 onward, the egg chamber changes shape as the oocyte grows, and, during stage 9, follicle cells rapidly migrate and change shape, processes that would likely be disrupted by the cell shape changes and cytokinesis associated with mitotic divisions. Indeed, cell division and migration have been shown to have an inimical relationship during gastrulation in Drosophila and Xenopus (GROSSHANS and WIESCHAUS 2000; MATA et al. 2000; SEHER and LEPTIN 2000; LEISE and MUELLER 2004).
We also found that the developmental timing of endocycle completion is maintained. Different cells completed endocycles at different times during late stage 9 to late stage 10A, consistent with their asynchronous entry into endocycles during stage 6 to stage 7. The timing of this endocycle arrest likely sets the stage for amplification, permitting the cell to dedicate its DNA replication machinery to rapid reduplication of only a few genomic regions.
In all species, stage 10B marked the onset of a synchronized amplification phase. Amplification foci appeared simultaneously in all follicle cells around the oocyte, but not in those around the nurse cells. We could not determine whether some amplification occurs before the amplification phase during endocycle S phases because nucleus-wide incorporation of BrdU would obscure detection of amplification foci. Indeed, earlier results suggested that the origin at the third chromosome chorion locus in D. melanogaster initiates more than once during the last endocycle S phase (CALVI et al. 1998). Nonetheless, our results suggest that a conserved developmental timer synchronizes follicle cell entry into a specialized amplification cell cycle phase.
It remains unclear, however, what coordinates morphogenesis of the egg chamber with the transition from endocycles into the amplification phase. In D. melanogaster, this coordination acts through the S-phase regulator cyclin E/Cdk2. Cyclin E levels oscillate with asynchronous follicle cell endocycle S phases, but then rise to high levels synchronously in all follicle cells at the onset of amplification (CALVI et al. 1998). Since follicle cells in D. melanogaster complete exactly three endocycles at different developmental times, some aspect of this coordination likely entails a cell-autonomous cell-cycle-counting mechanism. However, the strict spatial and temporal coordination of amplification onset with egg chamber morphogenesis suggests that developmental signaling pathways also contribute to this cell cycle transition. Our results suggest that both cell-autonomous and cell-nonautonomous mechanisms have been maintained during Drosophila evolution.
Evolution of developmental gene amplification:
Previous quantitative genomic Southerns had indicated that chorion genes amplify in several other Drosophila species and in the medfly C. capitata (MARTINEZ-CRUZADO et al. 1988; SWIMMER et al. 1990; VLACHOU et al. 1997; VLACHOU and KOMITOPOULOU 2001). We extend these results and show that the developmental coordination of this amplification is also conserved. Moreover, the appearance of more than two amplification foci in these other species suggests that, in addition to the major chorion protein genes, genes at other loci are amplified. Some of these loci may encode orthologs of the D. melanogaster genes at amplicons 30B and 62D. However, the appearance of more than four foci in some species suggests that additional, unknown loci are also amplified.
An alternative explanation for the extra foci is that the polyploid follicle cells in some species are not strictly polytene. However, we disfavor this interpretation for several reasons. First, polyteny is the default state for all polyploid cells in D. melanogaster, with only the nurse cells having an active mechanism to partially disperse polytene structure. Second, the bar-shaped morphology in these other species was comparable with D. melanogaster, suggesting that homologs and sister chromatids remain synapsed.
It remains possible that the extra amplicons that we detected in some species do amplify in D. melanogaster, but that a species-specific difference in the timing or level of their amplification makes them more apparent after BrdU labeling. Indeed, the size and intensity of the BrdU foci differed among species, suggesting that orthologs may amplify to different copy numbers. Future identification of these loci should provide insight into origin structure, regulation, and evolution and may identify new genes whose amplification is important for oogenesis.
Origin structure, epigenetic regulation, and ORC binding:
Despite a continued molecular and genetic dissection of origins in metazoa, unifying rules for origin anatomy remain largely unknown (ALADJEM et al. 2006 for review). The alignment of DNA sequences from 12 Drosophila genomes revealed islands of high-level conservation within the amplification origin at the third chromosome chorion locus. The most extensive conservation was a 71-nucleotide sequence in ACE3, which is also conserved upstream of the amplified cp18 ortholog in the medfly C. capitata (VLACHOU and KOMITOPOULOU 2001). This conservation is functionally significant because deletion of this sequence impairs amplification and the similar sequence from D. grimshawi can direct amplification in D. melanogaster (SWIMMER et al. 1990; BEALL et al. 2002; ZHANG and TOWER 2004). A DNA fragment from ACE3 that contains the conserved region was shown to bind ORC, further stressing its importance, but the specific DNA residues that ORC contacts are unknown (AUSTIN et al. 1999). The 71-nucleotide sequence resembles those found at other origins in that it is highly AT rich; otherwise, strict rules for a DNA consensus sequence at metazoan origins still do not apply.
Mounting evidence in a variety of organisms suggests that the epigenetic modification of chromatin is an important determinant of origin activity (MECHALI 2001 for review). The site-specific replication in stage 10B follicle cells represents an extreme example of origin developmental specificity. The evidence for conservation of nucleosome acetylation is consistent with a model that it plays an important role in origin function (AGGARWAL and CALVI 2004). This conserved acetylation is associated spatially and temporally with preferential ORC binding, consistent with the idea that these origins are, in part, epigenetically specified. Taken together, our results further suggest that this epigenetic modification may regulate origin developmental timing.
The most highly conserved sequences within ACE3 correspond to footprint sites for the Mip120 and Myb protein of the Myb–MuvB complex (BEALL et al. 2002). Previous studies in D. melanogaster and humans suggested that the Myb–MuvB complex activates and represses promoters and may have similar activities at origins (BEALL et al. 2004; KORENJAK et al. 2004; LEWIS et al. 2004). In D. melanogaster, mutation of the Myb gene, or deletion of the Myb- and Mip120-binding sites in ACE3, severely impairs amplification of the third chromosome locus (BEALL et al. 2002). Mutations in another protein of the Myb–MuvB complex, Mip130, resulted in inappropriate genomic replication in stage 10B follicle cells, suggesting that Myb–MuvB represses genomic origins (BEALL et al. 2004). Indeed, the Myb–MuvB complex contains the histone deacetylase enzyme Rpd3, whose mutation also results in genomic replication in stage 10B follicle cells (AGGARWAL and CALVI 2004; LEWIS et al. 2004). The conservation of DNA sequence in ACE3 suggests that Mip120 and Myb orthologs may regulate amplification origins in these other species. However, the entirety of the Myb site and the other two Mip120 sites in ACE3 are not well conserved. The difference in conservation between Myb- and Mip120-binding sites implies that, at least in some species, Mip120 binding plays the more prominent role in origin function. Alternatively, Myb may contribute, but the functional constraints on sequence and/or spacing for Myb DNA-binding sites may be relaxed and therefore not strictly conserved. Orthologs of the D. melanogaster Mip120, Myb, and other Myb–MuvB complex members are present in the other 11 sequenced Drosophila genomes (data not shown), but whether they bind and regulate amplification origins, and perhaps other origins, in these species awaits further investigation.
An important remaining question is what recruits acetylase activity to amplification origins. The conservation of origin acetylation, together with the high conservation of the Mip120 binding site, makes it tempting to speculate that the Myb–MuvB complex recruits acetylases to the origin. A cogent model is that developmental signaling pathways in follicle cells around the oocyte converge on the Myb complex to recruit acetylases and epigenetically regulate the amplification origins (LEWIS et al. 2004). Myb complexes are known to recruit acetylases to promoters, including those in human cancer cells (DAI et al. 1996; JOHNSON et al. 2002). The Drosophila orthologs of the retinoblastoma tumor suppressor (Rb) are also part of the Myb–MuvB complex at amplification origins and evidence supports that they may locally repress origins in follicle cells (BOSCO et al. 2001; BEALL et al. 2004). In human cells, Rb recruits histone deacetylases to repress promoters and has been shown to bind near some origins (KENNEDY et al. 2000; AVNI et al. 2003; FROLOV and DYSON 2004). Given the evidence for Rb and Myb in origin regulation, it may be that perturbed epigenetic regulation of origins contributes to genome instability in these cancers. A continued analysis that employs the genetics of D. melanogaster with the genomic information and tools now available for 11 sibling species should contribute to a deeper understanding of origin structure and regulation in metazoa.
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ACKNOWLEDGEMENTS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSLITERATURE CITED |
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LITERATURE CITED |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSLITERATURE CITED |
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