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. 2016 Feb 20:17:128.
doi: 10.1186/s12864-016-2444-5.

Cis regulatory motifs and antisense transcriptional control in the apicomplexan Theileria parva

Kyle Tretina  1 , Roger Pelle  2 , Joana C Silva  3
Affiliations

Cis regulatory motifs and antisense transcriptional control in the apicomplexan Theileria parva

Kyle Tretina et al. BMC Genomics. .

Abstract

Background: Theileria parva is an intracellular parasite that causes a lymphoproliferative disease in cattle. It does so by inducing cancer-like phenotypes in the host cells it infects, although the molecular and regulatory mechanisms involved remain poorly understood. RNAseq data, and the resulting updated genome annotation now available for this parasite, offer an unprecedented opportunity to characterize the genomic features associated with gene regulation in this species. Our previous analyses revealed a T. parva genome even more gene-dense than previously thought, with many adjacent loci overlapping each other, not only at the level of untranslated sequences (UTRs) but even in coding sequences.

Results: Despite this compactness, Theileria intergenic regions show a pattern of size distribution indicative of monocistronic gene transcription. Three previously described motifs are conserved among Theileria species and highly prevalent in promoter regions near or at the transcription start sites. We found novel motifs at many transcription termination sites, as well as upstream of parasite genes thought to be critical for host transformation. Adjacent genes that could be regulated by antisense transcription from an overlapping transcriptional unit are syntenic between T. parva and P. falciparum at a frequency higher than expected by chance, suggesting the presence of common, and evolutionary old, regulatory mechanisms in the phylum Apicomplexa.

Conclusions: We propose a model of transcription with conserved sense and antisense transcription from a few taxonomically ubiquitous and several species-specific promoter motifs. Interestingly, the gene networks regulated by conserved promoters are themselves, in most cases, not conserved between species or genera.

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Figures

Fig. 1
Fig. 1
Length of the three types of intergenic region (IGR) length in the genomes of T. parva, T. annulata, T. orientalis, and T. equi. IGR length, shown in base pairs, correlates with the directionality of the transcriptional units that flank them. Boxplot shows median (orange line), second and third quartiles (within box) and max value below 75 % + 1.5 interquartile range and minimum value above 25 % - 1.5 interquartile range (whiskers). Comparisons of intergenic region types within each species were significantly different than each other (0.001 < p < 0.005, two-tailed Student’s t-test)
Fig. 2
Fig. 2
Distribution of the TYAYWWW motif around transcription initiation sites. The horizontal axis represents sequence areas from -1,000 bp to +1,000 bp around transcription initiation sites with single nucleotide resolution. Position 0 represents the transcription initiation site, with a peak observed at the -3 position. The vertical axis represents the normalized frequency of the motif
Fig. 3
Fig. 3
Metrics of the top 3 motifs identified by MEME searches around transcription initiation sites. a The top three motifs (G-box, Spe2, and NFkB-like), their p-value identified by MEME, and their frequency in different genomic regions of four Theileria species and in the three types of intergenic regions (IGR) (Tp = Theileria parva; Ta = Theileria annulata; To = Theileria orientalis; Te = Theileria equi). b Distribution of the three motifs in the vicinity of transcription initiation sites in T. parva. All three motifs are located predominantly at or near transcription start sites (TSS)
Fig. 4
Fig. 4
Metrics of the top motif identified by MEME searches of transcription termination sites. a Motif 2 was conserved in tail-to-tail intergenic regions in four Theileria species (Tp = Theileria parva; Ta = Theileria annulata; To = Theileria orientalis; Te = Theileria equi) and b peaked in distribution at transcription termination sites genome-wide in T. parva. The horizontal axis represents sequence areas from -1,000 bp upstream to +1,000 bp downstream around transcription initiation sites with single nucleotide resolution. Position 0 represents the transcription termination site. The vertical axis represents the frequency of the motif
Fig. 5
Fig. 5
Length distribution of upstream open reading frames (uORFs) and reference open reading frames (rORFs). Only ORFs starting with a methionine were included in these distributions. Legend as in Fig. 1, with outliers are represented by ‘+’. Boxplot shows median (orange line), second and third quartiles (within box) and max value below 75 % + 1.5 interquartile range and minimum value above 25 % - 1.5 interquartile range (whiskers). uORF lengths were significantly lower than than rORF lengths (p < 0.001, two-tailed Student’s t-test)
Fig. 6
Fig. 6
The relationships of motifs found in T. annulata, T. equi, T. orientalis, T. parva, and B. bovis intergenic regions. The tree was created with STAMP and the tree generated with iTOL (Methods). A = Spe2 motif; B = G-box motif; C = NFkB-like motif
Fig. 7
Fig. 7
Theileria genes regulated by the G-box motif are enriched in genes that encoded secreted or transmembrane proteins
Fig. 8
Fig. 8
B. bovis genes regulated by the NFkB-like motif are enriched in genes that encoded transmembrane proteins
Fig. 9
Fig. 9
Reconstruction of turnover rate of three motifs from the present study. a G-box motif; b Spe2 motif; c NFkB-like motif. For each occurrence of a motif upstream of a gene in T. parva (Tp), T. annulata (Ta), T. orientalis (To) and T. equi (Te), we determined its distribution upstream of the ortologs in the other species, and infer the most parsimonious scenario for the number of acquisitions and losses of the motif in the branches leading to To, Ta and Tp. For example, a motif present upstream of the same ortholgous gene in To, Ta and Tp but absent in Te, is inferred to have arisen in the lineage leading to all the first three species, and hence be present at the node reflecting their most recent common ancestor. Motifs present in Te and one of the other species could have been lost twice, or lost once and regained, and so are deamed “undetermined”
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