Multiple independent evolutionary solutions to core histone gene regulation
© Mariño-Ramírez et al.; licensee BioMed Central Ltd. 2006
Received: 8 August 2006
Accepted: 21 December 2006
Published: 21 December 2006
Core histone genes are periodically expressed along the cell cycle and peak during S phase. Core histone gene expression is deeply evolutionarily conserved from the yeast Saccharomyces cerevisiae to human.
We evaluated the evolutionary dynamics of the specific regulatory mechanisms that give rise to the conserved histone regulatory phenotype. In contrast to the conservation of core histone gene expression patterns, the core histone regulatory machinery is highly divergent between species. There has been substantial evolutionary turnover of cis-regulatory sequence motifs along with the transcription factors that bind them. The regulatory mechanisms employed by members of the four core histone families are more similar within species than within gene families. The presence of species-specific histone regulatory mechanisms is opposite to what is seen at the protein sequence level. Core histone proteins are more similar within families, irrespective of their species of origin, than between families, which is consistent with the shared common ancestry of the members of individual histone families. Structure and sequence comparisons between histone families reveal that H2A and H2B form one related group whereas H3 and H4 form a distinct group, which is consistent with the nucleosome assembly dynamics.
The dissonance between the evolutionary conservation of the core histone gene regulatory phenotypes and the divergence of their regulatory mechanisms indicates a highly dynamic mode of regulatory evolution. This distinct mode of regulatory evolution is probably facilitated by a solution space for promoter sequences, in terms of functionally viable cis-regulatory sites, that is substantially greater than that of protein sequences.
Core histone genes encode four families of proteins that package DNA into the nucleosome, which is the basic structural unit of eukaryotic chromosomes . The four core histones are H2A, H2B, H3 and H4, and each nucleosome consists of 146 base-pairs (bp) of DNA wrapped around an octameric core containing two copies of each histone protein. Comparative studies of core histones have revealed that their sequences are among the most evolutionary conserved of all eukaryotic proteins . For instance, the human H4 protein (NP_003539) is 92% identical to its yeast Saccharomyces cerevisiae ortholog (NP_014368) . The high levels of core histone sequence conservation are thought to be due to severe structural constraints imposed by their assembly into the histone octamer  as well as the similar functional constraints across species associated with the compact binding of DNA .
Most of the packaging of genomic DNA by core histones occurs primarily during the S phase of the cell cycle, when DNA is being actively replicated; stoichiometrically appropriate levels of histone proteins are required to bind DNA immediately following replication . As such, the expression of core histone genes is tightly regulated and peaks sharply during S phase . Much like the histone sequences, this histone gene expression pattern is highly conserved among eukaryotes ranging from human to the yeasts Saccharomyces cerevisiae and Schizosaccharomyces pombe [8–13].
The studies that resulted in the characterization of these motifs and transcription factors have led to the elucidation of core histone gene regulation in model experimental systems such as S. cerevisiae. For example, the yeast transcription factor Spt10p was recently demonstrated to activate core histone gene expression . Interestingly, the SPT10 gene was originally identified as a suppressor of Ty insertion mutations [24, 25] and as a global regulator of core promoter activity . However, despite the fact that Spt10p affects the expression of hundreds of yeast genes, it specifically binds cis-regulatory sequences, referred to as upstream activating elements, which are found only in core histone gene promoters. Thus, the global regulatory properties of Spt10p are based solely on changes in levels of core histone gene expression. In support of this model of histone gene regulation, the DNA-binding domain of Spt10p was recently characterized and shown to mediate sequence-specific interaction with the core histone gene upstream activating element . There are a number of such examples, from S. cerevisiae and other model systems, of efforts to characterize experimentally the mechanisms of core histone gene regulation. In addition, efforts are underway to investigate core histone promoters among different species computationally .
Despite the substantial body of knowledge on the regulation of core histone genes, little is known about the evolutionary dynamics that have given rise to these regulatory mechanisms. We present here an evolutionary analysis of core histone gene regulatory mechanisms. The emphasis of this work is placed on understanding the evolution of cis-regulatory sites along with their cognate transcription factors. We analyzed the phyletic distributions of 14 experimentally verified core histone cis-regulatory elements among 24 crown group eukaryotes. The evolution of core histone gene cis-regulatory sites and transcription factors is considered in light of core histone protein sequence and structure evolution. Despite the highly conserved core histone sequences and expression patterns, the mechanisms of histone gene regulation were found to be highly divergent and lineage specific. The implications of this dissonance with respect to the evolution of gene regulatory systems are explored.
Results and discussion
Gene expression patterns
Lineage-specific cis-regulatory mechanisms
Distribution of core histone regulatory motifs among human and yeast
Phyletic distribution of core histone transcription factors
RefSeq accession (protein name) a
Phyletic distribution b
Metazoans and plants
Metazoans and plants
In order to evaluate the evolution of core histone promoter cis-regulatory sites in more detail, the phyletic distribution of all 14 experimentally characterized DNA binding motifs among 24 crown group eukaryotic species was assessed. To do this, position frequency matrices (PFMs) of the cis-regulatory motifs (Figure 1) were taken from the TRANSFAC database  or were generated from the binding site alignments reported in the original citation. Intergenic promoter regions of core histones (H2A, H2B, H3, and H4) for all 24 species were then searched for the presence of the 14 cis-regulatory motifs using the program CLOVER . CLOVER uses the cis-regulatory site PFMs to evaluate the promoter sequences for statistically significant over- or under-representation of motif elements. For any given promoter sequence (P i ), CLOVER assigns a numerical value (raw score) to each cis motif (j) indicating its over- or under-representation in that sequence. The distribution of cis-regulatory motifs in that promoter is then represented as a vector, P i = (P i1, P i2 ... P i14], of sequence- and motif-specific CLOVER scores (P ij ). The CLOVER-generated vectors were then compared using the Pearson correlation coefficient (r). High r values would thus represent two promoter sequences with similar cis-regulatory binding sites. The r values were transformed into pair-wise promoter distances using the following formula: d = 1 - (r + 1)/2.
Motif evolutionary dynamics
Sequence and structure evolution
The lineage-specific pattern of core histone promoter evolution revealed by the comparative analysis of cis-regulatory motif sequences stands in contrast to the evolution of core histone protein sequences and structures. There are four families of core histone proteins, namely H2A, H2B, H3 and H4, and these families are present in all eukaryotes, indicating that they probably evolved via three ancient gene duplication events that preceded the diversification of the eukaryotic lineage. Given this evolutionary scenario, it can be expected that all protein sequences (structures) of a given family will be more closely related to one another, regardless of the species from which they are derived, than they are to members of other families. Straightforward sequence comparison methods, such as BLASTP , bear this expectation out (data not shown). In fact, although sequences within families are highly conserved, it is not possible to identify members of different families using pair-wise BLASTP comparisons. On the other hand, despite its low sequence similarity among core histones, the histone fold domain (HFD) is present in all four core histones [34, 35].
A more detailed analysis of the evolutionary relationships within and between histone protein families was performed using a comparative analysis of the HFD. The HFD is represented in the Pfam database, and an alignment of its representative members has been used to generate a hidden Markov model (HMM) that captures the position-specific sequence variation characteristic of the domain. In order to build a multiple sequence alignment that unites members of all four families, representative members of each family from the 24 species analyzed here were aligned in register to the HFD-HMM. This HFD multiple sequence alignment was then used to calculate all pair-wise distances, within and between families, and to build a HFD phylogeny (Figure 8c). As expected, all members within any given family are more closely related to one another than to members of any other family. The phylogenetic relationships within families are largely consistent with the established taxonomic relationships of the species from which the sequences were derived. However, the relatively high within-family sequence identities, as well as the level of resolution afforded by the between-family HMM approach, do not lend themselves to robust delineation of evolutionary relationships within families. Perhaps most germane is the fact that the between-family relationships illustrated by the HFD-HMM approach are identical to those seen in the DALI structural comparison. It is worth reiterating that these family-specific protein sequence relationships are totally discordant with the largely lineage-specific promoter sequence element relationships.
We have demonstrated a striking dissonance between the deep evolutionary conservation of core histone regulatory phenotypes and the profound divergence of their regulatory mechanisms. Core histone genes exhibit similar cell cycle (S phase specific) expression patterns from the yeast S. cerevisiae to human (Figure 2). This regulatory conservation is consistent with the high levels of sequence conservation among core histone proteins. Nevertheless, the regulatory mechanisms that are used to achieve the conserved expression patterns of core histone genes are almost entirely lineage specific. The cis-trans machinery involved in core histone gene regulation has changed substantially between lineages through gain and loss of transcription factor proteins and their cognate binding sites. This suggests that, for families like the core histone genes, phylogenetic footprinting  may have limited utility for identifying functional regulatory elements across all but the most closely related species.
There are additional regulatory elements that may help to achieve coordinated regulation of core histone genes in metazoans. For instance, a sequence found in core histone gene encoding regions is important for their expression and may serve as an internal promoter element common to the mammalian lineage [41–43]. In addition, the transcription factor NPAT has been implicated as a global regulator of core histone gene expression among metazoans even though it does not seem to bind any DNA sequence directly [44–46]. This may provide yet another global lineage specific regulatory mechanism that distinguishes the metazoan mode of core histone gene regulation from that of yeast.
Even though the four core histone gene families (H2A, H2B, H3, and H4) diverged before the species studied here, the regulatory mechanisms are more similar for different family members within species than for the same family members between species (Figures 4 and 5). Thus, there is a kind of concerted regulatory evolution operating between members of different core histone gene families. This pattern stands in stark contrast to the pattern of core histone sequence evolution, whereby members of the same family are more similar to one another across species reflecting their more recent common ancestry (Figure 8). This suggests that very different modes of evolution exist for histone gene regulation versus protein sequence and structure. The solution space for promoter sequence evolution (the space of functionally viable cis-regulatory binding site sequences) may be far more vast than that of core histone protein sequences. This results in a much more dynamic evolutionary paradigm for promoter sequences and the transcription factors proteins that bind them. Purifying selection may be less efficacious at eliminating variants of cis-regulatory sites because a number of sequence variants may bind transcription factors with similar affinities. In addition, new cis-regulatory sites, which are short and degenerate by nature, may arise relatively quickly through mutation along the promoter. It is possible that these new variants can lead to an exploration of expression space and rapid fixation of adaptive variants by positive selection. Adaptive expression changes of this type may be facilitated by the emergence of intermediate redundant regulatory programs that maintain the ancestral expression pattern and function while simultaneously allowing for selective testing of novel expression patterns . Such an evolutionary mode, with less pronounced purifying and more prominent adaptive selection, could explain the observation that novel cis-trans combinations are subject to substantial turnover and may be regularly reinvented among evolutionary lineages. In addition, the inherent evolutionary flexibility of regulatory systems may allow for coordinated within-species changes that respond to epistatic pressure from other regulatory pathways in the same lineage that share transcription factors.
It is currently unclear whether the turnover of regulatory mechanisms, in the face of conserved expression patterns, is unique to core histones or also occurs for other gene families. Some studies on the evolution of gene regulation do report evidence of conserved regulatory sequences and expression patterns [47, 48], whereas others indicate that gene regulatory networks do in fact diverge rapidly [49–51]. However, regulatory divergence usually leads to distinct expression patterns [51–53]. Interestingly, although yeast core histone transcripts include polyA tails, core histone transcripts are unique among metazoan transcripts in that they lack polyA tails. The absence of polyA tails, which are often bound by poly(A)-binding proteins to promote translation initiation, may necessitate, to some extent, species-specific solutions to core histone gene regulation.
The comparative genomics of core histone gene regulation reveal a novel evolutionary mode, which we dub 'circuitous evolution'. Circuitous evolution of core histone gene regulation is distinct from convergent evolution, because the conservation of the core histone gene regulatory patterns suggests that the same pattern existed in the last common ancestor of all species analyzed here. After divergence from the last common ancestor, the core histone expression patterns remained unchanged but the regulatory mechanisms that give rise to the conserved phenotype diverged dramatically. Thus, with respect to core histone gene regulation, where you are from and where you are are far more important than how you get there.
As an addendum, during revision of the manuscript we became aware of a recently published paper , which confirms that the specific periodic pattern of core histone gene expression is uniquely evolutionarily conserved. The report by Jensen and coworkers also demonstrates how many different regulatory solutions have evolved to control the periodic expression of integrated biological systems that function in the cell cycle.
Materials and methods
Core histone protein coding sequences were obtained from the histone database . A list of species from which the sequences were obtained is provided in Additional data file 3. Core histone protein coding sequences were used as queries in a series of tblastn  searches against species-specific National Center for Biotechnology (NCBI) Entrez Genome project databases  in order to locate the precise genomic regions of core histones. Entrez Genome project species-specific databases include complete Reference Sequence (RefSeq) genomes when available or whole genome shotgun sequence entries when RefSeq versions are unavailable. Core histone proximal promoter sequences were taken as 1 kilobase upstream of the annotated translational start site. For bidirectional promoters, the entire intergenic regions (range 133 to 970 bp; average 413 bp) were taken for analysis. Promoter sequences are provided as Additional data file 1. The nomenclature reported by Marzluff and coworkers  was used for the human and mouse core histone genes.
Cis-regulatory binding sites
The DNA binding subunits of the transcription factor proteins and their cognate cis-regulatory binding sites were taken from the published literature as described in the Introduction and Results and discussion sections. PFMs of the cis-regulatory motifs were taken from the TRANSFAC database  or, when not available, generated from the binding site alignments reported in the original citation. The PFMs were used with the program CLOVER  to search the core histone promoter regions for the presence of the cis-regulatory motifs. The complete set of CLOVER predictions is provided in Additional data file 4. CLOVER output was used to construct promoter-specific vectors composed of scores of over-represented and/or under-represented cis sites for each sequence; the vectors were then used to compare promoter sequences with pair-wise Pearson correlation coefficients. CLOVER also gives the position of each predicted motif and these positions were normalized by the length of the promoter sequence to give the relative lengths shown in Figure 7 panels a, c and e. Locations were randomly sampled from a uniform distribution in order to generate the negative control plots shown in Figure 7 panels b, d and f.
The TFBS Perl modules  were used to further analyze cis-regulatory sequence binding motifs. For each cis-regulatory motif, sequences of all the motif sites predicted by CLOVER were extracted and aligned. These alignments were used to construct PFMs, which were converted to position weight matrices by normalizing with background nucleotide frequencies. Information content per cis-regulatory sequence motif position , taken from the position weight matrices, were used to build sequence logos with the program WebLogo .
Protein sequence and structure
Core histone protein sequences were taken from the histone database . Protein sequences are provided in Additional data file 2. A probabilistic HMM representing the HFD found in all core histone proteins [34, 35] was taken from the Pfam database . The HFD (Pfam accession number: PF00125) was extracted from each core histone protein sequence using the HMM with the program HMMER . The core histone HFD multiple sequence alignment was built by aligning each HFD sequence back to the PF00125 HMM, thus preserving the same structural register for all HFD domain sequences. The program QuickTree  was used to build a neighbor joining tree  from the HFD multiple sequence alignment.
A three-dimensional structure of the nucleosome core, PDB ID:1KX5 , used for comparison was taken from the RCSB Protein Data Bank . Structural comparisons between the individual core histone proteins were performed using the fold classifications computed in the Dali database [37, 64]. Z scores between individual core histone proteins were taken and converted to pairwise distances (d) by normalizing with the self-similarity Z score using the following equation:
Gene expression data were taken from reports published elsewhere [8–13]. For Figure 2, relative expression levels (log2 ratios) for S. cerevisiae were plotted against cell cycle time points, and visualization was done using matrix2png .
Additional data files
The following additional data are available with the online version of this article. Additional data file 1 contains the promoter sequences of core histone genes used in the study. Additional data file 2 contains the core histone protein sequences used in the study. Additional data file 3 contains the list of species used in the study. Additional data file 4 contains the CLOVER predictions for all core histone gene promoters used in the study.
The authors would like to thank Alex Brick and Geoffrey Watson for their assistance in obtaining core histone intergenic regions during their internships at NCBI and Boris E Shakhnovich for helpful discussions. We are grateful to two anonymous reviewers for valuable comments and suggestions. This study utilized the high-performance computational capabilities of the Biowulf PC/Linux cluster at the National Institutes of Health, Bethesda, Maryland, USA . The authors wish to thank several anonymous reviewers for very helpful comments and suggestions. This research was supported by the Intramural Research Program of the NIH, NLM, and NCBI.
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