Multiple independent evolutionary solutions to core histone gene regulation

Abstract

Background: 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.

Results: 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.

Conclusion: 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.

Figure 1

Core histone gene cis-regulatory sequence motifs and transcription factors. Experimentally verified cis-regulatory motifs and their transcription factors were taken from the literature as described in the Introduction section (see text). Sequence logos for the cis-motifs show information content (conservation) per position. Unidentified transcription factors are indicated by NI. TF, transcription factor.

Figure 2

Cell cycle (S phase) specific expression patterns of core histone genes. A cluster of eight core histone genes and their relative expression levels are plotted along the progression time of the cell cycle for the yeast S. cerevisiae.

Figure 3

Schema for core histone gene promoters. (a) Four different human core histone gene promoters are shown along with the relative locations of predicted cis-binding motifs. Official gene names are indicated for each promoter. These are examples of genes that are not divergently transcribed because a pair of divergently transcribed genes share identical motifs. (b) Yeast (S. cerevisiae) bidirectional core histone promoters and cis-binding motifs. The promoter sequences and, accordingly, the location/presence of the cis-motifs of individual members of each family may vary for each gene. Not drawn to scale.

Figure 4

Relationships among core histone gene promoter sequences. Promoter sequences are related by comparisons of cis-regulatory motif vectors, as described in the text. Individual promoters are ordered by similarity along each axis. Pair-wise correlations between promoter-specific vectors are color coded according to the scale bar shown. The block color structure along the diagonal reveals clusters of related promoter sequences.

Figure 5

Relationships among species-specific cis-regulatory motif sets. (a) Species are related by comparisons of cis-regulatory motif vectors as described in the text. Individual sets of promoters are grouped by species, which are then ordered by similarity along each axis. Pair-wise correlations between species vectors are color coded according to the scale bar shown. (b) Randomized promoter sets preserving both mono- and dinucleotide sequence composition is shown for comparison.

Figure 6

Distribution of cis-regulatory motifs among Saccharomycetales. Species are ordered according to their taxonomic relationships and presence/absence of three motifs is shown, along with their sequence logos.

Figure 7

Relative positions of cis-regulatory motifs among Sacchromycetales core histone gene promoters. The relative location of each motif is shown along with its raw CLOVER score; only motifs with scores ≥6 are shown. Relative positions are shown for (a) Spt10, (c) NEG, and (e) TBP. (b, d, f) Randomized distributions of motif positions are shown for comparison.

Figure 8

Core histone protein structure and sequence evolution. (a) Structural relationships between the four core histone protein families. (b) Three-dimensional nucleosome structure is shown with each core histone chain colored: H2A, orange; H2B, yellow; H3, blue; and H4, green. (c) Sequence relationships within and between the four core histone protein families. Internal nodes that set-off each core histone family are color coded using the same scheme used for the nucleosome structure. The tree is rooted with archaeal histone-like sequences (white internal node).

Figure 9

Structure and conservation of the histone 3'-UTR stem loop. (a) Schema of the 3'-UTR stem loop structure present in metazoan mRNAs. (b) Sequence logo representation of the histone 3'-UTR stem loop. The sequences (accession number: RF00032) were obtained from the Rfam database [68]. UTR, untranslated region.