Multifunctional RNA-binding proteins influence mRNA abundance and translational efficiency of distinct sets of target genes

PLoS Comput Biol. 2021 Dec 8;17(12):e1009658. doi: 10.1371/journal.pcbi.1009658. eCollection 2021 Dec.

Abstract

RNA-binding proteins (RBPs) can regulate more than a single aspect of RNA metabolism. We searched for such previously undiscovered multifunctionality within a set of 143 RBPs, by defining the predictive value of RBP abundance for the transcription and translation levels of known RBP target genes across 80 human hearts. This led us to newly associate 27 RBPs with cardiac translational regulation in vivo. Of these, 21 impacted both RNA expression and translation, albeit for virtually independent sets of target genes. We highlight a subset of these, including G3BP1, PUM1, UCHL5, and DDX3X, where dual regulation is achieved through differential affinity for target length, by which separate biological processes are controlled. Like the RNA helicase DDX3X, the known splicing factors EFTUD2 and PRPF8-all identified as multifunctional RBPs by our analysis-selectively influence target translation rates depending on 5' UTR structure. Our analyses identify dozens of RBPs as being multifunctional and pinpoint potential novel regulators of translation, postulating unanticipated complexity of protein-RNA interactions at consecutive stages of gene expression.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Computational Biology
  • Gene Expression Regulation / genetics*
  • Humans
  • Myocardium / cytology
  • Protein Biosynthesis / genetics*
  • RNA, Messenger / genetics*
  • RNA, Messenger / metabolism
  • RNA-Binding Proteins / genetics*
  • RNA-Binding Proteins / metabolism

Substances

  • RNA, Messenger
  • RNA-Binding Proteins

Grants and funding

This work was supported by the European Union’s Horizon 2020 research and innovation programme [European Research Council (ERC) advanced grant, grant agreement n° AdG788970 to N.H.; https://erc.europa.eu]; the Leducq Foundation [11 CVD-01 to N.H.; https://www.fondationleducq.org]; and the "Bundesministerium für Bildung und Forschung" [grant CaRNAtion to N.H; https://www.dfg.de]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.