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Discriminating between HuR and TTP binding sites using the k-spectrum kernel method
BACKGROUND:The RNA binding proteins (RBPs) human antigen R (HuR) and Tristetraprolin (TTP) are known to exhibit competitive binding but have opposing effects on the bound messenger RNA (mRNA). How cells discriminate between the two proteins is an interesting problem. Machine learning approaches, such as support vector machines (SVMs), may be useful in the identification of discriminative features. However, this method has yet to be applied to studies of RNA binding protein motifs. RESULTS:Applying the k-spectrum kernel to a support vector machine (SVM), we first verified the published binding sites of both HuR and TTP. Additional feature engineering highlighted the U-rich binding preference of HuR and AU-rich binding preference for TTP. Domain adaptation along with multi-task learning was used to predict the common binding sites. CONCLUSION:The distinction between HuR and TTP binding appears to be subtle content features. HuR prefers strongly U-rich sequences whereas TTP prefers AU-rich as with increasing A content, the sequences are more likely to be bound only by TTP. Our model is consistent with competitive binding of the two proteins, particularly at intermediate AU-balanced sequences. This suggests that fine changes in the A/U balance within a untranslated region (UTR) can alter the binding and subsequent stability of the message. Both feature engineering and domain adaptation emphasized the extent to which these proteins recognize similar general sequence features. This work suggests that the k-spectrum kernel method could be useful when studying RNA binding proteins and domain adaptation techniques such as feature augmentation could be employed particularly when examining RBPs with similar binding preferences
Comparative life cycle transcriptomics revises Leishmania mexicana genome annotation and links a chromosome duplication with parasitism of vertebrates
Leishmania spp. are protozoan parasites that have two principal life cycle stages: the motile promastigote forms that live in the alimentary tract of the sandfly and the amastigote forms, which are adapted to survive and replicate in the harsh conditions of the phagolysosome of mammalian macrophages. Here, we used Illumina sequencing of poly-A selected RNA to characterise and compare the transcriptomes of L. mexicana promastigotes, axenic amastigotes and intracellular amastigotes. These data allowed the production of the first transcriptome evidence-based annotation of gene models for this species, including genome-wide mapping of trans-splice sites and poly-A addition sites. The revised genome annotation encompassed 9,169 protein-coding genes including 936 novel genes as well as modifications to previously existing gene models. Comparative analysis of gene expression across promastigote and amastigote forms revealed that 3,832 genes are differentially expressed between promastigotes and intracellular amastigotes. A large proportion of genes that were downregulated during differentiation to amastigotes were associated with the function of the motile flagellum. In contrast, those genes that were upregulated included cell surface proteins, transporters, peptidases and many uncharacterized genes, including 293 of the 936 novel genes. Genome-wide distribution analysis of the differentially expressed genes revealed that the tetraploid chromosome 30 is highly enriched for genes that were upregulated in amastigotes, providing the first evidence of a link between this whole chromosome duplication event and adaptation to the vertebrate host in this group. Peptide evidence for 42 proteins encoded by novel transcripts supports the idea of an as yet uncharacterised set of small proteins in Leishmania spp. with possible implications for host-pathogen interactions