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Nucleic Acids Research Pages 427-430

Evidence for an early prokaryotic origin of histones H2A and H4 prior to the emergence of eukaryotes
Introduction
Materials And Methods
   Purification of M.kandleri histone
   N-terminal sequencing of MkaH
   Cloning and sequencing of the hmk gene
   Phylogenetic reconstruction
Results And Discussion
Acknowledgements
References


Evidence for an early prokaryotic origin of histones H2A and H4 prior to the emergence of eukaryotes

Evidence for an early prokaryotic origin of histones H2A and H4 prior to the emergence of eukaryotes Alexei I. Slesarev1,3,*, Galina I. Belova1, Sergei A. Kozyavkin2 and James A. Lake3

1M. M. Shemyakin and Yu. A. Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 117871 Moscow, Russia, 2Fidelity Systems, Inc., Gaithersburg, Maryland 20879, USA and 3Molecular Biology Institute and MCD Biology, University of California, Los Angeles, Los Angeles, CA 90095, USA

Received October 17, 1997; Revised and Accepted November 25, 1997

DDBJ/EMBL/GenBank accession no. AF034206

ABSTRACT

Histones have been identified recently in many prokaryotes. These histones, unlike their eukaryotic homologs, are of a single uniform type that is thought to resemble the archetypal ancestor of the eukaryotic histone family. In this paper we report the finding, the cloning and the phylogenetic analysis of the sequence of a prokaryotic histone from the hyperthermophile Methanopyrus kandleri. Unlike previously described prokaryotic histones, the Methanopyrus sequence has a novel structure consisting of two tandemly repeated histone fold motifs in a single polypeptide. Sequence analyses indicate that the N-terminal repeat is most closely related to eukaryotic H2A and H4 histones, whereas the C-terminal repeat resembles that found in prokaryotic histones. These results imply an early divergence within the histone gene family prior to the emergence of eukaryotes and may represent an evolutionary step leading to eukaryotic histones.

INTRODUCTION

DNA-binding proteins with sequences homologous to eukaryotic histones were first discovered and extensively characterized in methanogens (1-4) and have been subsequently observed in Pyrococcus and Thermococcus isolates (5,6). To date, 15 complete prokaryotic histone sequences are available (7,8). Uniformly, the prokaryotic histones are of a single type that is thought to resemble the common ancestor of the eukaryotic histone family.

The NMR structure of HMfB, one of two homologous histones from Methanothermus fervidus, has been solved recently (9). The structure consists of three [alpha]-helices within the histone fold motif found in eukaryotes (10,11), providing further evidence that prokaryotic histones are homologous to eukaryotic core histones. It was also shown that in vitro HMfA and HMfB proteins of M.fervidus compact DNA so that it moves faster in an electrophoretic mobility shift assay (EMSA) (2), protect multiples of 60 bp DNA fragments from a nuclease digestion (4) and induce toroidal supercoils in closed circular DNA (12), a kind of DNA packaging which may resemble the DNA structure in eukaryotic nucleosomes.

We have been studying proteins influencing topological properties of DNA in the hyperthermophile Methanopyrus kandleri. This prokaryote, isolated from the abyssal `black smoker' environment, is able to grow up to 110°C hemolithoautotrophically on H2 and CO2 (13,14), and possesses a striking combination of DNA topoisomerases (15-17). While characterizing DNA binding proteins from Methanopyrus we observed and isolated a novel protein. From its partial N-terminal amino acid sequence we tentatively identified it as a prokaryotic histone. To investigate this protein further it was cloned from a genomic Methanopyrus library and sequenced. We found that the Methanopyrus histone, unlike other prokaryotic histone genes, is a two-domain histone consisting of two tandemly repeated histone fold motifs in a single polypeptide. Sequence analyses indicated that the N-terminal domain is more closely related to eukaryotic histones H2A and H4 than to other prokaryotic histones. These results imply that an early divergence within the histone gene family occurred prior to the emergence of eukaryotes and may represent an evolutionary step leading to eukaryotic histones.

MATERIALS AND METHODS

Purification of M.kandleri histone

Histone (MkaH) was purified from M.kandleri strain AV19 (14). Initial purification steps (cell lysis, sulfate fractionation, phosphocellulose and heparin chromatography) were as described for topoisomerase V isolation (16). MkaH eluted from heparin-Sepharose column at ~0.8 M NaCl, slightly ahead of DNA topoisomerase V (1 M NaCl). After the heparin chromatography, fractions containing MkaH were concentrated and the concentrate was passed through a Superdex 75 PG column (Pharmacia), equilibrated with 30 mM Tris-HCl, pH 8.0 at 25°C, 0.5 M NaCl, 5% glycerol, 2 mM [beta]-mercaptoethanol. The resulting fractions containing MkaH were used for N-terminal sequencing. Protein concentrations were determined spectrophotometrically. Protein composition of the fractions was analyzed by SDS-PAGE. Gels were stained using a Bio-Rad Silver stain kit or Coomassie G-250.

To monitor MkaH binding to DNA, an aliquot containing MkaH protein was incubated with 0.2 µg of a supercoiled plasmid in 30 mM Tris-HCl, pH 8.0 at 25°C, 1 M potassium glutamate at 80°C for 10 min. Products were analyzed by electrophoresis on a 1% agarose gel.

N-terminal sequencing of MkaH

About 10 µg of MkaH (Superdex 75 fraction) were separated from contaminating proteins by SDS-PAGE and electroblotted onto PVDF membrane (Millipore). A corresponding band was cut out and subjected to 50 cycles of Edman degradation on an Applied Biosystems 471A protein sequencer.

Cloning and sequencing of the hmk gene

Genomic DNA of M.kandleri was prepared as described (18). A partial Sau3A1 digest and a commercial preparation of lambda EMBL3 arms (Stratagene) were used for the lambda library construction according to the manufacturer's recommendations. Escherichia coli XL1 Blue MRA carrying bacteriophage P2 (Stratagene) was used as a host for propagation of lambda phage. The flanking seven amino acid stretches of the 40 amino acid N-terminal sequence were used to prepare degenerate oligonucleotide primers. These primers were used to generate by PCR a 120 bp nucleotide probe for cloning of hmk. The uniformly labelled PCR probe was prepared using the QuickPrime kit (Pharmacia) and ([alpha]-32P)dCTP (NEN). With this probe ~1000 plaques were screened, and eight separate lambda clones were isolated. The hmk gene was cloned on a 1 kb BamH1 fragment. This fragment was subcloned into pBluescript II SK(+), generating pMkaH, and then used as a template for DNA sequencing. The problems in sequencing of GC-rich (60%) Methanopyrus DNA were resolved by the addition of ThermoFidelase (Fidelity Systems) to AmpliCycle kit (Perkin Elmer). The MkaH sequence within the cloned 1052 bp BamHI genomic fragment was identified by comparing the translation product with the N-terminal 40 amino acid sequence from the purified protein. The resulting protein (starting with Met in the N-terminal 40 amino acid sequence of MkaH) is composed of 154 residues, giving a molecular mass of 17 004 Da which is in agreement with SDS-PAGE data (18 kDa).


Figure 1. Heparin-Sepharose chromatography of MkaH. Phosphocellulose pool IVa of topoisomerase V (see Fig. 1 in ref. 16) was chromatographed on a 5 ml HiTrap heparin-Sepharose column. (A) Column elution profile of the pool IVa. Fractions containing MkaH are shaded. (B) MkaH activity of the heparin-Sepharose fractions. Native pBR322 (0.2 µg) was incubated with 1 µl of each fraction under standard conditions and electrophoresed in 1.5% agarose gel with 1.6 µg/ml chloroquine. Marked bands are: open circular DNA (OC); negatively supercoiled DNA (-SC); positively supercoiled DNA (+SC); relaxed DNA topoisomers (rel). (C) The protein pattern of selected fractions containing MkaH. An equal volume of each fraction (5 ml, 0.05-0.2 µg of protein/lane) was electrophoresed on a 4-15% SDS-polyacrylamide gel and stained by silver. Positions of topoisomerase V (TV) and MkaH are indicated.

Phylogenetic reconstruction

The 16 taxon, phylogenetic tree shown in Figure 2 was obtained using the Bootstrappers Gambit algorithm (19) applied to parsimony and distance analyses. Two hundred bootstrap trees were calculated to determine the 50% majority-rule consensus tree, each search was initiated with 100 replicates of random taxon edition, and positions with gaps were excluded. For all methods four-point metrics were used to assess quartet values; the quartet consistency value (19), 53.46%, was selected to ensure that the probability of finding the best solution was >99.9%. The Methanococcus jannaschii histone sequence Mja H0168 was used as the outgroup, assuming that the tree of life is rooted within the eubacteria (20). Since site-to-site variation was judged to be significant, distances were corrected for this artifact by estimating nine site categories from the data, calculating distances from the eight non-constant categories, and estimating trees from the sums of the distances (21,22).

Based on empirical studies of bootstrap analyses, they represent highly conservative estimates of phylogenetic accuracy. Typically for maximum parsimony, bootstrap proportions of >= 70% correspond to a probability of >= 95% that the respective clade is a historical lineage. Hence only bootstrap values >50% are shown. For Gambit the probabilities are slightly less conservative.

RESULTS AND DISCUSSION

In the course of purification of DNA topoisomerase V from M.kandleri we noticed a substantial change in the electrophoretic mobility of supercoiled and open circular DNA after incubation with early topoisomerase V fractions (16) and tentatively ascribed the aberrant migration of DNA to its binding with histone-like proteins. The DNA binding activity could be separated from topoisomerase V activity by heparin-Sepharose chromatography (Fig. 1). The 18 kDa protein, designated as MkaH (Fig. 1), that produced the abnormal mobility of supercoiled and open circular DNA was purified and its partial N-terminal amino acid sequence has been determined (see Materials and Methods). The N-terminal sequence of the protein was MAVELPKAAIERIFRQGIGERRLSQDAKDTIYDFVPTMAE. We compared this protein sequence with sequences in the non-redundant database using the BLAST algorithm (National Center for Biotechnology Information) and found that the sequence is closely related to previously characterized histones from methanogens and to eukaryotic H4 and H2A histones. However, the molecular mass of the protein (18 kDa) is twice as large as known prokaryotic histones, which have molecular masses from 7 to 9 kDa (1-3,23,24). To investigate this protein further the hmk gene was cloned (described in Materials and Methods).


Figure 2. Multiple sequence alignment of prokaryotic histone and eukaryotic H2A and H4 sequences. Parts of sequences containing the histone fold motif are boxed. The sequence of the N-terminal domain of the M.kandleri histone (MkaH-N) is shaded. Also shaded are residues in other sequences which are identical to the corresponding MkaH-N residues. The numbers indicate the positions of the last residue shown in the Figure. The 78th residue (tyrosine) of the M.kandleri histone is omitted. The major structural elements ([alpha]-helices) of the histone fold motif are summarized at the bottom of the alignment. ALSCRIPT, version 2.0 (37), was used to format the alignment. The full organism names and accession numbers for the corresponding sequences are as follows: Sce, Saccharomyces cerevisiae (J01325, X00724); Tth, Tetrahymena thermophila (L18892, X00417); Mka, Methanopyrus kandleri (AF034206); Mfe, Methanothermus fervidus (M96826, M34778); Mth, Methanobacterium thermoautotrophicum (M90086, M86663); Py, Pyrococcus strain GB-3 (U08837, U08838); TAN1, Thermococcus strain AN1 (S82196); Mfo, Methanobacterium formicicum (U12929, U12930, U12931); Mja, Methanococcus jannaschii (L77118, L77117, U67536, U67566, U67474).

MkaH contains two equal length homologous domains (Fig. 2). These appear to be products of a direct repeat, and are related by 27.6% amino acid identity. Unlike other methanogens and Pyrococcus GB-3a which contain several highly homologous histones encoded by separate genes (1,3,25), we could find no evidence of additional MkaH related proteins in M.kandleri using the Southern blot hybridization of the hmk gene with M.kandleri genomic DNA digested with different restriction enzymes (not shown).

The sequences of the M.kandleri N- and C-terminal domains are shown in Figure 2 aligned with the prokaryotic type of histone sequences and with eukaryotic H2A and H4 sequences. To understand the evolutionary relationships among the various histones, a majority-rule consensus tree was derived from phylogenetic reconstructions (Fig. 3). Three reconstruction methods were used including paralinear (logdet) distances, maximum parsimony and Jukes-Cantor distances. Paralinear (logdet) distances (22,26) were emphasized because of their generality (most distance methods are special cases of paralinear distances). Within this tree the eukaryotic histones, H2A and H4, and the N-terminal repeat of the Methanopyrus histone (Mka H-N) form a clade that is distinct from the remaining prokaryotic histones. This clade is supported by bootstrap values of 81, 98 and 68%, corresponding to the paralinear, maximum parsimony and Jukes-Cantor algorithms, respectively, which are interpreted as strongly supporting this part of the tree. (A `rule of thumb' is that a bootstrap value of >70% corresponds to approximately the 95% confidence level that a node is correct).


Figure 3. The phylogenetic tree illustrating histone gene relationships. The tree was deduced from the 16 sequences shown in the alignment in Figure 2. The topology shown here is that of a majority rule consensus tree combining the results from three individual majority rule consensus trees derived using the following methods: paralinear/logdet distances, maximum parsimony and Jukes-Cantor distances. The numbers next to the central branches represent the percent of bootstrap replicates supporting the clades for these methods, respectively (from top to bottom).

The tree also groups the Pyrococcus and Thermococccus sequences (Py H1, Py H2 and TAN1 H1) as a separate clade that is supported by high bootstrap values (77, 100 and 93%, respectively). The grouping is consistent with the prokaryotic phylogenetic trees derived from analyses of ribosomal DNA and elongation factor EF-1[alpha] sequences (20,27,28).

Since it is well known that phylogenetic trees are sensitive to artifacts of alignment, we also considered alternative alignments. In particular, we analyzed three additional alignments which differ slightly from the one shown in Figure 2 in that they use fewer gaps. All alignments supported the association of the N-terminus of the Methanopyrus histone sequence (Mka H-N) with eukaryotic H2A and H4 sequences at similar or higher bootstrap values (data not shown). Hence we regard these data as strongly supporting the relationship of the N-terminal domain of MkaH to eukaryotic histones H2A and H4.

The C-terminal domain of the Methanopyrus histone (Mka H-C) is not grouped with the eukaryotic histones but is a separate lineage within the group of existing prokaryotic histones. Because of the short lengths of the histone sequences we can not resolve its position more accurately. A horizontal gene transfer of eukaryotic histones to M.kandleri can not be ruled out but it would not be the most parsimonious explanation and we consider it unlikely. Hence, we interpret this result to imply that the part of the sequence found at the Methanopyrus N-terminus has duplicated to form its eukaryotic homologs.

Over the past two decades it has been established that the local structure of DNA is different in eukaryotes and prokaryotes. In prokaryotic cells, DNA is torsionally stressed, while eukaryotes convert most of the torsional constraints of DNA into writhe using the histone-containing nucleosome and the relaxing type1B topoisomerase I (29-36). It may be, therefore, significant that a new type of histone resembling eukaryotic histones H2A and H4 exists in M.kandleri since M.kandleri also contains DNA topoisomerase V, a prokaryotic counterpart of eukaryotic topoisomerase I (15). Thus, several major elements of the eukaryotic DNA packaging mechanism appear to have been present in prokaryotes prior to the emergence of eukaryotes.

ACKNOWLEDGEMENTS

We thank Karl Stetter and Martin Gellert for their initial support of this work. The work was supported by an International Research Scholar Award of the Howard Hughes Medical Institute, by the US Civilian Research and Development Foundation under Award No. RB1-248 and by a grant from the Russian Foundation for Basic Research (to A.I.S.) and by grants from the National Science Foundation and National Institutes of Health (to J.A.L.)

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*To whom correspondence should be addressed. Tel: +7 095 336 4200; Fax: +7 095 336 4200; Email: slesarev@ibch.siobc.ras.ru

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