Sars International Centre for Marine Molecular Biology, Bergen High Technology Centre, Bergen, Norway
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Abstract |
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Introduction |
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Specific amino acid residues in the histone tails can be covalently modified through acetylation, methylation, phosphorylation, poly(ADP-ribosylation), and ubiquitination. These alterations may change interactions of the histone tails with DNA or other regulatory proteins (or both). It has been proposed that different combinations of these modifications on individual nucleosomes, or over regions of chromatin, may be an epigenetic code that is interpreted by downstream protein complexes in carrying out nuclear activities (Jeppesen 1997
; Strahl and Allis 2000
; Turner 2000
). The code also may be important in mechanisms of cell memory in maintaining patterns of gene expression after mitotic cell division and in defining restricted outcomes in development and cellular differentiation. Current understanding of the histone code is extremely rudimentary, but already certain residues appear to have crucial importance. For example, acetylation of lysine 9 in the N-terminal tail of histone H3 favors the location of the associated locus in euchromatin, whereas methylation of this same residue is more characteristic of an address in heterochromatic regions (Nakayama et al. 2001
; Rice and Allis 2001
).
The regulatory repertoire of chromatin is not restricted to covalent modifications of histone tails and also includes the use of distinct histone variants. The use of variants is regulated both spatially and temporally. Homologues of the mammalian histone H3like variant CENP-A occur throughout eukaryotes and are specifically found in centromeric regions of chromatin (Sullivan 2001
). The variant H2A-Bbd is markedly deficient on the inactive X chromosome of mammalian cells (Chadwick and Willard 2001
), a chromosome that also is enriched in hypoacetylated histone H4 (Jeppesen and Turner 1993
). On a more local scale, the H2A.Z variant is preferentially linked to intergenic DNA in yeast at the PHO5 and GAL1 loci, and the extent of linkage varies with the state of transcriptional activation (Santisteban, Kalashnikova, and Smith 2000
). In a temporal sense, one of the earliest observations on histone variants was the use of specific subtypes during cleavage stages at the onset of embryonic development. In the sea urchin, developmental variants of histones H2A, H2B, and linker histone H1 have been described (Mandl et al. 1997
). Embryonic variants of histone H1 also have been found in Xenopus (Dworkin-Rastl, Kandolf, and Smith 1994
), Drosophila (Ner and Travers 1994
), and most recently, the mouse (Tanaka et al. 2001
) and may be a general feature of early development. Later in development, the use of H1° linker variants in terminally differentiated cells also appears to be a common feature in a number of organisms.
The requirement to package newly synthesized DNA into chromatin makes it logical that histone synthesis is regulated in concert with the cell cycle, and it has been observed that the abundance of histone mRNA increases 25- to 30-fold at the G1-S transition (Osley 1991
; Ewen 2000
). These replication-dependent histone mRNAs are intronless and are not polyadenylated but instead contain a conserved 16-nt stem-loop structure at the 3' end (Dominski and Marzluff 1999
). The promoters of the replication-dependent histone genes usually contain core RNA polymerase II elements, a distal activation domain, and subtype-specific consensus elements that link promoter activity to the cell cycle. A second class of histone mRNAs is expressed at constitutive basal levels throughout the cell cycle, and these are both polyadenylated and can contain introns. These mRNAs encode the so called "replacement variant" histones implicated in chromatin repair and remodeling. The stoichiometric relationship of histone mass to DNA content might lead to expectation of some correlation between histone gene content and genome size; but thus far, no such relationship is obvious. High copy number tandem repeats of histone clusters do occur in some species with rapid cycles of DNA replication during early development, suggesting that histone gene organization may be related more to certain life history characteristics than to phylogenetic position, but the data remain limited. Overall, despite the large number of histone sequences available for a variety of organisms, information on histone gene complements and organization remains fragmentary in all but a few species, and evolutionary trends are unclear.
One significant phylogenetic gap in information on histone gene structure and organization is in the subphylum Urochordata. Of the five sister Urochordate classes, the Appendicularia (fig. 1 ) has interesting life history features with respect to histone gene organization, histone gene regulation, and spatial and temporal use of histone variants. The animal begins its short life cycle with very rapid cell cycles, but after metamorphosis, growth occurs almost entirely by increasing cell size through endoreduplication rather than mitotic cell division. Polyploidization, a process that is much more common in both plants and animals than is generally recognized, exceeds 1,000n in some tissues of the appendicularian genus Oikopleura (Fenaux 1971
; Ganot and Thompson 2002
) and raises questions concerning the decoupling of major histone synthesis from regular cell cycle progression. The accessible and transparent epithelium responsible for repeated synthesis of the elaborate houses in which the animal lives and filter feeds contains fields of cells with characteristic, distinctive variations in nuclear morphologies (Spada et al. 2001
; Thompson, Kallesoe, and Spada 2001
). This organ is ideally suited to exploring the spatial nuclear compartmentalization of histone variants, relative to defined patterns of gene expression.
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Materials and Methods |
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In vitro fertilizations were performed by collecting oocytes from mature females in watch glasses and adding a diluted suspension of sperm obtained from 1 to 2 mature male ejaculates in sterile filtered seawater. Fertilized oocytes were rinsed two to three times in sterile filtered seawater when 90% of them had emitted polar bodies. Embryos were then left to develop at room temperature.
Genomic Library Screening
A partial O. dioica shotgun genomic database was searched for core histone sequences, and one partial H2A sequence was retrieved. Primers OdH2Ap1, 5'-GATGTTGGGTAGAACACCACC-3', and OdH2Ap2, 5'-GGACTCCAGTTCCCCGTTGG-3', were designed from this sequence to amplify a 250-bp fragment spanning the histone fold. This fragment was random prime labeled with 32P--dCTP and used to screen a genomic library that had been prepared by partial digestion of sperm DNA with Sau 3A and cloned into the lambda EMBL3 vector (Stratagene). Among positive clones obtained from this screening, a clone containing a five-histone cluster was used for producing probes for H1 and the other core histones (H2B, H3, and H4). A 241-bp HindIII or HindII fragment spanning the histone H1 globular domain was purified and used for further screening of the genomic sperm DNA library.
Quantitative Southern Blotting
Haploid genomic DNA was isolated from sperm, and 4-µg aliquots were digested with EcoRV, SpeI-SphI, or NcoI-BamHI. A genomic clone containing a five-histone cluster was loaded on the same gel as a copy number standard. After electrophoresis and transfer, the DNA was UVcross-linked to the wet membrane (Nylon Hybond N+, Amersham) with 150 mJ/cm2 at 254 nm, using a Hoefer UVC 500 Ultraviolet Crosslinker (APBiotech). Probes spanning the histone fold of OdH2A, OdH2B, OdH3, OdH4, and the globular domain of OdH1 were labeled as above. Hybridizations were carried out overnight at 55°C in 6x SSC, 1% nonfat dried milk, 1% SDS, and 2.5 mM EDTA. Final washing was in 0.5x SSC, 0.5% SDS at 65°C. Hybridized blots were imaged with a FLA2000 phosphoimager (Fuji), and signal quantification was done using Image Gauge v2.01 software (Fuji).
Bacterial Artificial Chromosome and cDNA Library Screening
The bacterial artificial chromosome (BAC) library was prepared by partial HindIII digestion of sperm DNA. The BAC clones were spotted in ordered grids onto nylon filters (Amplicon Express, Washington). The cDNA library was prepared from polyA+ RNA isolated from early tadpoles, as described previously (Spada et al. 2001
). The libraries were screened using probes spanning the globular domain of the linker histone H1 and the histone fold domains of H2A and H4. Hybridizations and washing steps were carried out as described above. Signals from hybridized filters were recorded on autoradiographic films (Kodak Biomax MS). For reprobing, BAC library filters were stripped by submerging them in boiling water0.5% SDS for 15 min. Single-colony excision was performed on isolated plaques from the cDNA library to obtain DNA fragments cloned in pBK-CMV.
Reverse TranscriptasePolymerase Chain Reaction
Total RNA from indicated developmental stages was isolated by the guanidium thiocyanateacid phenol method. First strand cDNA synthesis was performed by incubating 2 µg of DNaseI-treated (PCR grade, GIBCO-BRL, Life Technologies) total RNA with 100 pmol of random hexamers, 10 mM DTT, 1 U/µl RNasin (Promega), 0.5 mM dNTPs, in 50 mM Tris-HCl75 mM KCl3 mM MgCl2, pH 8.3, for 1 h at 37°C in the presence or absence of 400 U of MMLV reverse transcriptase (GIBCO-BRL, Life Technologies). Each PCR reaction contained cDNA synthesized from an equivalent of 50 ng of total RNA, 0.4 U Vent polymerase (New England Biolabs), 0.2 mM of each dNTP, 0.2 µM primers, in 25 µl of 10 mM KCl, 20 mM Tris-HCl pH 8.8, 10 mM (NH4)2SO4, 2 mM MgSO4, and 0.1% Triton X-100. After initial denaturation for 2 min at 95°C, 35 amplification cycles (95°C, 30 s; 5063°C [primer dependent, see table 1
], 30 s; 72°C, 30 s) were carried out with a final extension for 5 min at 72°C. All RT-negative controls were run to 40 cycles of amplification. Primers used for the specific RT-PCR reactions are described in table 1
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Results |
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EMBL accession numbers for all sequences reported in this study are from AJ494848 to AJ494856.
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Discussion |
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No clear correlation has been observed between the total histone gene complement of an organism and its genome size. The data from O. dioica agree that if any such correlative constraint does exist, it is very weak. Despite an estimated genome size of 72 Mb (Seo et al. 2001
) compared with 3,200 Mb for humans (International Human Genome Sequencing Consortium 2001
), O. dioica has a total histone gene complement that is very similar to that of humans. Thus, size of the histone gene complement does not appear to be a major factor that regulates the stoichiometry of histone to DNA content in the cell nucleus. One trend that has appeared previously is that organisms undergoing embryonic development with rapid, early cleavage cycles have extended tandem repeats of histone gene clusters, whereas those with longer cleavage stage cell cycles, such as mammals, do not. Tandem histone gene cluster repeats are found both in rapidly developing organisms with relatively small genome sizes such as Drosophila (Lifton et al. 1978
; Matsuo and Yamazaki 1989
) and in those with large genomes such as Xenopus (Perry, Thomsen, and Roeder 1985
; Turner et al. 1988
). Oikopleura dioica diverges from this trend in that it has very rapid cleavage cycles (510 min duration at 20°C) during early development but does not contain extended tandem histone gene repeats.
It is not surprising that with respect to a broad range of species, O. dioica histones H3 and H4 are highly conserved in both the histone fold and in the regulatory N-terminal tails. Thus far, most investigations of the histone code have concentrated on modifications of the N-terminal tails of H3 and H4. There is logic to this in that the high level of conservation implies that findings in one or a few species are likely to be generalized to many others. It also may imply, however, that these modifications will be primarily implicated in more basal processes in chromatin remodeling. The greater variability among diverse organisms in H2A and H2B sequences may reflect less functional constraint on these proteins or a greater variety of more specialized functions layered on to the regulatory roles of H3 and H4 (or both). Specific variants of H2A are known to be vital to the viability of some organisms, suggesting that at least some more specialized roles are critical for development and survival (Clarkson et al. 1999
). There is a much greater degree of variability within the set of O. dioica H2A sequences, particularly in the N- and C-terminal tails, than among the H2A complements found in vertebrates or in invertebrates, such as Drosophila and Caenorhabditis elegans, where sufficient sequence information is available for comparison. Curiously, the extent of variation in O. dioica H2A sequences resembles that found in phylogenetically distant plants such as rice (Oryza sativa, TIGR rice genome database, http://www.tigr.org/tdb/e2k1/osa1) or Arabidopsis (TIGR A. thaliana genome database, http://www.tigr.org/tdb/e2k1/ath1). In plants, polyploidization is a frequent occurrence and is particularly prevalent in species with small genome sizes (De Rocher et al. 1990
). Oikopleura dioica also makes extensive use of polyploidization in its development and rapid growth (Ganot and Thompson 2002
), and a speculative correlation might link this aspect to the common greater diversity observed in H2A sequences in such distant organisms. The stage-specific expression of the H2A variants in O. dioica warrants further investigation in this regard.
The organization of histone genes in O. dioica shares features found in other organisms, including quintets with a central H1 gene flanked by pairs of divergently transcribed H3-H4 and H2A-H2B pairs as well as more isolated variants. At a total length of 3.5 kb, the quintet cluster is the most compact reported thus far, and high gene density appears to be a general feature of the O. dioica genome (Seo et al. 2001
). The shared promoter regions of divergently transcribed histone genes were very small, ranging from 220 to 240 bp in length. In mitotically dividing cells, where most studies of histone synthesis have been carried out, primary regulation of transcription and translation occurs near the G1-S cell cycle transition. In O. dioica, after metamorphosis at 14 h of development, growth through the remainder of the life cycle occurs principally through endoreduplication of DNA and increased cell size rather than through mitotic cell division. Thus, this organism provides an appealing system for examining regulation of histone synthesis in an endoreduplicating as opposed to a mitotic environment. One notable feature in the regulatory regions of several O. dioica histone genes is the absence of an appropriately positioned TATA box upstream of the transcription start site. This is the case for genes that are indeed transcriptionally active (fig. 9
). Elements found in the promoters of histone genes described in other species also are present in the O. dioica promoters. The shared promoter regions of divergently transcribed O. dioica H2A-H2B gene pairs can be divided into two classes as has been done for the shared H2A-H2B promoters in human and mouse (Albig et al. 1999
). The human and murine type I promoters contain TATA boxes, Oct-1 elements, and CAAT boxes, whereas the type II promoters contain in addition E2F and CREB elements. The E2F element is characteristic of S-phaseregulated genes (La Thangue 1994
), and the CREB element may adjust H2A and H2B expression to fluctuating growth conditions (Trappe, Doenecke, and Albig 1999
). In human type II promoters, there is an additional octanucleotide RT-1 element adjacent to the E2F element (Albig et al. 1999
). Database searches by these authors revealed this sequence to be unique to human H2A-H2B promoters. The O. dioica type I H2A-H2B promoters lack CAAT boxes when compared with the mammalian counterparts. The type II promoters contain the E2F and CREB elements as well as the RT-1 box described thus far only in human promoters. By running a PRATT analysis on promoter sequences in databases, we confirmed the absence of this element in promoters other than those of human and O. dioica. In O. dioica, the RT-1 box is not immediately adjacent to the E2F element, but interestingly, it is present in promoters that lack a TATA box 5' of the H2A gene and absent in promoters that contain the TATA box. Among genes coding for the O. dioica H2A.1 variant, examples of both type I and type II promoters were found. This variant was expressed throughout development. On the other hand, promoters of the H2A.2 and H2A.4 variants were of type I, lacking cell cycledependent elements, and were expressed exclusively in day 4 and 5 animals, a time when most growth of the animal occurs through endoreduplication rather than through mitotic division.
Processing of histone mRNA has been most extensively studied using echinoderm sea urchin and mammalian sequences. The replication-dependent histones are up-regulated at G1-S, and this involves a conserved stem-loop structure in the 3'UTR. Replacement variants lack the stem-loop structure, are polyadenylated, and are expressed at more basal levels throughout the cell cycle. Important factors in processing replication-dependent histone RNAs are the stem-loopbinding protein and the U7 snRNP. Positioning of U7 is determined by RNA-RNA base pairing between U7 and a purine-rich element (HDE) that serves as a molecular guide in defining the point of cleavage (Scharl and Steitz 1994
). The HDE is located 1317 nucleotides downstream of the cleavage site that itself is immediately 3' of the stem-loop sequence in the histone 3'UTR. The HDE sequence is strictly conserved (CAAGAAAGA) in the sea urchin where it was first described (Georgiev and Birnstiel 1985
) but is more variable around a consensus core AAAGAG sequence in mammals (Dominski and Marzluff 1999
). Inspection of the flybase reveals that in Drosophila there is not a strictly conserved HDE consensus sequence but there are clearly purine-rich stretches in the 3'UTRs of the histone genes in the appropriate location downstream of the stem-loop structure. Analysis of C. elegans histone gene sequences in the wormbase reveals no consensus HDE sequence or purine-rich stretch downstream of the stem-loop. In O. dioica, there also was no evidence of an HDE consensus sequence or purine-rich element 3' of the stem-loop. In contrast, inspection of the sequence database for the related urochordate ascidian Ciona intestinalis (http://bahama.jgi-psf.org/prod/bin/blast.ciona.cgi) revealed a clear putative consensus core HDE element (AAAGAGA for H2A, H3, and H4; AAA[G/C]GAG for H1 and H2B). The U7 snRNA of echinoderms and vertebrates is small (5570 nt), but thus far, no U7 candidates or obvious orthologues of the U7-specific Sm protein Lsm10 have been identified in the genomic sequences of Drosophila and C. elegans (Lanzotti et al. 2002
). Despite lacking an HDE element, we did verify that cleavage at the normal site 3' of the stem-loop does occur in O. dioica histone H4 messages. It remains to be determined whether U7-like snRNA sequences are involved in the processing of Drosophila, C. elegans, and O. dioica histone mRNAs. Phylogenetically, it is intriguing that histone genes in the echinoderm sea urchin, the urochordate ascidian, and higher vertebrates all have HDE elements, whereas the appendicularian O. dioica does not.
In the O. dioica histone gene complement, there were frequently AATAAA polyadenylation signals downstream of the stem-loop sequence. This also is characteristic of the Drosophila and C. elegans histone genes, and it has been proposed that this might serve as a safeguard to prevent read-through into neighboring histone genes with the generation of antisense RNA (Lanzotti et al. 2002
). We have shown in this study that O. dioica transcripts can contain both the stem-loop sequence and a polyA tail. This has been observed in other species, for example, Drosophila (Lanzotti et al. 2002
) and bovine (Gendron et al. 1998
). In Drosophila embryos, mutants for the stem-loopbinding protein accumulate polyadenylated histone mRNA. The turnover of polyadenylated RNA in this case appeared to be dependent on cell type, and the stability of the polyA transcripts was more pronounced in proliferating or endoreduplicating cells than in quiescent G0 cells. There was a clear decrease in O. dioica H1.1/2 gene expression that paralleled the transition from growth by cell proliferation to growth through endoreduplication, but there was no evident qualitative shift in the use of polyadenylation for any of the histone variants examined (fig. 9
). The functional significance, if any, of the O. dioica histone transcripts containing both the stem-loop and a polyA tail is at present unclear.
The packaging of DNA into nucleosomes is a fundamentally conserved property of the eukaryotic nucleus, and this is evident in the conservation of histone sequences, particularly those of the central H3-H4 tetramer. In contrast, there appears to be much more plasticity in the organization of histone gene complements among organisms, the degree of variation within histone subclasses, the regulation of histone gene expression, and perhaps some of the fundamentals of histone mRNA processing. The results here show that differences can be quite marked even over relatively short phylogenetic distances (e.g., echinoderm-appendicularian-ascidian) and that similarities may be linked more to certain life history or cell biological characteristics of an organism. With the increasing number of eukaryotic genome sequences coming available, studies of these aspects would appear to be an important complement to the current focus on deciphering the histone code in a few selected organisms.
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Acknowledgements |
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Footnotes |
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Keywords: U7 snRNP
RT-1 box
histone stem-loop
Appendicularia
histone polyadenylation
histone promoter
Address for correspondence and reprints: Eric M. Thompson, Sars International Centre for Marine Molecular Biology, Bergen High Technology Centre, Thormøhlensgt. 55, N-5008 Bergen, Norway. E-mail: eric.thompson{at}sars.uib.no
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