Genome-wide analysis of 3′-untranslated regions supports the existence of post-transcriptional regulons controlling gene expression in trypanosomes

Abstract

In eukaryotic cells, a group of messenger ribonucleic acids (mRNAs) encoding functionally interrelated proteins together with the trans-acting factors that coordinately modulate their expression is termed a post-transcriptional regulon, due to their partial analogy to a prokaryotic polycistron. This mRNA clustering is organized by sequence-specific RNA-binding proteins (RBPs) that bind cis-regulatory elements in the noncoding regions of genes, and mediates the synchronized control of their fate. These recognition motifs are often characterized by conserved sequences and/or RNA structures, and it is likely that various classes of cis-elements remain undiscovered. Current evidence suggests that RNA regulons govern gene expression in trypanosomes, unicellular parasites which mainly use post-transcriptional mechanisms to control protein synthesis. In this study, we used motif discovery tools to test whether groups of functionally related trypanosomatid genes contain a common cis-regulatory element. We obtained conserved structured RNA motifs statistically enriched in the noncoding region of 38 out of 53 groups of metabolically related transcripts in comparison with a random control. These motifs have a hairpin loop structure, a preferred sense orientation and are located in close proximity to the open reading frames. We found that 15 out of these 38 groups represent unique motifs in which most 3′-UTR signature elements were group-specific. Two extensively studied Trypanosoma cruzi RBPs, TcUBP1 and TcRBP3 were found associated with a few candidate RNA regulons. Interestingly, 13 motifs showed a strong correlation with clusters of developmentally co-expressed genes and six RNA elements were enriched in gene clusters affected after hyperosmotic stress. Here we report a systematic genome-wide in silico screen to search for novel RNA-binding sites in transcripts, and describe an organized network of several coordinately regulated cohorts of mRNAs in T. cruzi. Moreover, we found that structured RNA elements are also conserved in other human pathogens. These results support a model of regulation of gene expression by multiple post-transcriptional regulons in trypanosomes.

The globalization of messenger RNA regulation

“…Among the recent advances in this field are the dozens of ‘developmental’ RNA regulons discovered in trypanosomes that dynamically change during different periods of the life cycle, for example, differentiation in the blood steam by coordinating the expression and stability of RNAs encoding metabolic as well as structural proteins (reviewed in [15]). In addition, the early discoveries of the PUF (PUm-Fbf) family of RNA regulons in Pat Brown’s lab at Stanford have continued to advance up the phylogenetic scale to include mammalian Pum1 and Pum2 RBPs (reviewed in [13]), and developmental RNA regulons among the STAR-GLD-1 and GLD2 RBP family in C. elegans (discussed in [16]).…”

Post-transcriptional RNA regulons affecting cell cycle and proliferation

“…Many RNA regulons have also been discovered using genetic approaches while others were observed as dynamic patterns of mRNA co-regulation during a regulatory event. The trypanosome life cycle field has employed this latter method extensively, followed by identifying the key RBPs or global coordinators [5,16,28]. Through these techniques, many examples of RNA regulons have emerged over the past decade at nearly every step of post-transcriptional RNA processing, including splicing, export, translation, RNA stability and localization [6,10].…”

Characterization of the mRNA untranslated regions [UTR] of the Trypanosoma cruzi LYT1 isoforms derived by alternative trans-splicing

“…The UTRs, mainly the 3' UTR regions, have been shown to play crucial roles in the posttranscriptional mechanisms of gene regulation [48]. Indeed, the knowledge and regulatory elements annotation of these regions could get insights into their role.…”