RNA regulons and the RNA-protein interaction network

Abstract

The development of genome-wide analysis tools has prompted global investigation of the gene expression program, revealing highly coordinated control mechanisms that ensure proper spatiotemporal activity of a cell ' s macromolecular components. With respect to the regulation of RNA transcripts, the concept of RNA regulons, which -by analogy with DNA regulons in bacteria -refers to the coordinated control of functionally related RNA molecules, has emerged as a unifying theory that describes the logic of regulatory RNA-protein interactions in eukaryotes. Hundreds of RNA-binding proteins and small non-coding RNAs, such as microRNAs, bind to distinct elements in target RNAs, thereby exerting specifi c and concerted control over posttranscriptional events. In this review, we discuss recent reports committed to systematically explore the RNA-protein interaction network and outline some of the principles and recurring features of RNA regulons: the coordination of functionally related mRNAs through RNAbinding proteins or non-coding RNAs, the modular structure of its components, and the dynamic rewiring of RNA-protein interactions upon exposure to internal or external stimuli. We also summarize evidence for robust combinatorial control of mRNAs, which could determine the ultimate fate of each mRNA molecule in a cell. Finally, the compilation and integration of global protein-RNA interaction data has yielded fi rst insights into network structures and provided the hypothesis that RNA regulons may, in part, constitute noise ' buffers ' to handle stochasticity in cellular transcription.

Post-transcriptional RNA regulons affecting cell cycle and proliferation

“…In addition to these early confirmations of the RNA regulon model, many additional distinct biological processes, pathways and macromolecular complexes across the three domains of life have been shown to be regulated together at the mRNA level, and in nearly every case regulatory RBPs involved in coordinating these functions were identified [3,10,13,61] (see review articles noted above). Below, we focus on cell cycle functions in yeast and mammalian cells that are potentially coordinated as RNA regulons at the levels of RNA export and translation/stability.…”

“…There have been various examples of RNA regulons found in cell lines and several that appear to coordinate various processes in tissues and organs [3,10,13]. Indeed, one would expect that RNA regulons would be an efficient mechanism to optimize multicellular organismal development and several examples are in the literature.…”

“…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]. …”

Mechanisms coordinating ELAV/Hu mRNA regulons

“…Gene expression is coordinated by three known mechanisms: i) DNA operons/regulons, ii) promoter-based transcription initiation, and iii) RNA operons/regulons [4,9,39-41]. In bacteria, DNA operons represent genes that function together and are physically grouped on the chromosome, but also by transcription factors that function at each promoter site.…”

“…Many techniques and procedures have been devised to examine the coordinated changes in mRNAs. These methods include Selex based on natural sequences [5], RIP-chip/seq [6], CLIP [7], PAR-CLIP [8] and other methods of RNP enrichment and RNA turnover [reviewed in 4,9,10]. However, the detailed mechanisms that determine how RBPs bind to coding and noncoding regions of multiple mRNAs allowing them to orchestrate global outcomes of protein production are poorly understood.…”