Four RNA families with functional transient structures

Abstract

P rotein-coding and non-coding RNA transcripts perform a wide variety of cellular functions in diverse organisms. Several of their functional roles are expressed and modulated via RNA structure. A given transcript, however, can have more than a single functional RNA structure throughout its life, a fact which has been previously overlooked. Transient RNA structures, for example, are only present during specific time intervals and cellular conditions. We here introduce four RNA families with transient RNA structures that play distinct and diverse functional roles. Moreover, we show that these transient RNA structures are structurally well-defined and evolutionarily conserved. Since RFAM annotates one structure for each family, there is either no annotation for these transient structures or no such family. Thus, our alignments either significantly update and extend the existing RFAM families or introduce a new RNA family to RFAM. For each of the four RNA families, we compile a multiplesequence alignment based on experimentally verified transient and dominant (dominant in terms of either the thermodynamic stability and/or attention received so far) RNA secondary structures using a combination of automated search via covariance model and manual curation. The first alignment is the Trp operon leader which regulates the operon transcription in response to tryptophan abundance through alternative structures. The second alignment is the HDV ribozyme which we extend to the 5 0 flanking sequence. This flanking sequence is involved in the regulation of the transcript's self-cleavage activity. The third alignment is the 5 0 UTR of the maturation protein from Levivirus which contains a transient structure that temporarily postpones the formation of the final inhibitory structure to allow translation of maturation protein. The fourth and last alignment is the SAM riboswitch which regulates the downstream gene expression by assuming alternative structures upon binding of SAM. All transient and dominant structures are mapped to our new alignments introduced here.

Deciphering the Universe of RNA Structures and trans RNA–RNA Interactions of Transcriptomes In Vivo: From Experimental Protocols to Computational Analyses

“…Mazloomian and Meyer (2015)), may assume more than a single functional RNA structure or trans RNA-RNA interaction throughput its cellular life (e.g. Zhu and Meyer 2015;Lai et al 2013) and, in particular, is unlikely to ever experience true thermodynamic equilibrium as a naked RNA. In particular for long RNAs such as coding transcripts, there is no reason to assume that they fold into a minimum-free energy structure spanning the entire transcript.…”

“…that a single transcript can encode and express not just one, but several distinct RNA structures which are differentially expressed depending on the specific in vivo environment. Known cases do include examples not only from bacteria, but also from model organisms such as the fruit fly (Steif and Meyer 2012;Zhu et al 2013;Zhu and Meyer 2015;Mazloomian and Meyer 2015). There is, for example, strong statistical evidence for differentially expressed, local RNA structure features near splice sites that define tissue-specific splice isoforms (Mazloomian and Meyer 2015).…”

A genetic selection reveals functional metastable structures embedded in a toxin-encoding mRNA

“…Although recent advances using in vivo probing at the genome scale have confirmed 517 that translation efficiency strongly correlates with the mRNA structure around the RBS 518 (Mustoe et al, 2018), little is known about the influence of co-transcriptional folding on 519 translation. Bacteria could, in principle, reduce or delay the translation of a specific 520 mRNA by playing with its secondary structure while the mRNA is being made (Lai,521 Proctor, & Meyer, 2013; Zhu & Meyer, 2015). In this article, we identified two functional 522 RNA hairpins within a type I toxin-encoding mRNA for which a tight control of 523 translation is essential.…”

In silico methods for co-transcriptional RNA secondary structure prediction and for investigating alternative RNA structure expression

“…Transient features may not only help to efficiently guide the emerging RNA structure towards "good" folding pathways that yield the desired structural configuration(s) [35], but can also play dedicated, additional functional roles [34,36]. Recent in silico analyses show that transient RNA structure features can be evolutionarily as conserved as the final RNA secondary structure and that these transient features can be computationally predicted [37,38]. The succession of RNA secondary structure for a given transcript as function of time defines a so-called folding pathway.…”

“…Goal 1 is currently the most challenging to achieve. We present initial results showing that transient RNA struc-ture features are evolutionarily conserved and can be computationally predicted in Zhu et al [37,38]. The underlying computational pipeline is concisely described below in order to be easily reproducible.…”