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RNA Regulons and the RNA-Protein Interaction Network

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RNA Regulons and the RNA-Protein Interaction Network BioMol Concepts, Vol. 3 (2012), pp. 403–414 • Copyright © by Walter de Gruyter • Berlin • Boston. DOI 10.1515/bmc-2012-0016 Review RNA regulons and the RNA-protein interaction network Jochen Imig 1, a , Alexander Kanitz 1, a and Introduction Andr é P. Gerber 1,2, * In 1961, Fran ç ois Jacob and Jacques Monod described 1 Institute of Pharmaceutical Sciences , Department of the fi rst gene regulatory system in E. coli – the bacterial Chemistry and Applied Biosciences, ETH Zurich, lac operon (1) . An operon refers to a single, polycistronic CH-8093 Zurich , Switzerland transcriptional unit composed of a cluster of functionally 2 Department of Microbial and Cellular Sciences , Faculty and/or structurally related genes that are under the control of Health and Medical Sciences, University of Surrey, of a single regulatory unit that can be activated or repressed Guildford GU2 7XH , UK by a trans -acting factor. The operon concept was revolution- * Corresponding author ary as it implied that transcriptional units might bear infor- e-mail: [email protected] mation for the coordinate expression of functionally related proteins. Such an integrative architecture enables prokaryotes to quickly coordinate gene expression in response to environ- Abstract mental stimuli. However, DNA operons limit the fl exibility to regulate the expression of genes individually and would The development of genome-wide analysis tools has prompted therefore be detrimental to the regulation of genes that have global investigation of the gene expression program, reveal- multiple functions. ing highly coordinated control mechanisms that ensure proper DNA operons, which lead to the production of polycis- spatiotemporal activity of a cell ’ s macromolecular compo- tronic transcripts, predominantly occur in prokaryotes (2) . In nents. With respect to the regulation of RNA transcripts, the contrast, most eukaryotic genes are monocistronic, with their concept of RNA regulons, which – by analogy with DNA own promoter and transcription terminators at the 5 ′ - and regulons in bacteria – refers to the coordinated control of 3 ′ -ends, respectively. So, how is the coordinated expression functionally related RNA molecules, has emerged as a unify- of functionally related genes achieved in eukaryotes ? The ing theory that describes the logic of regulatory RNA-protein answer is certainly complex because such coordination is seen interactions in eukaryotes. Hundreds of RNA-binding pro- at all stages of gene expression, from chromatin structure and teins and small non-coding RNAs, such as microRNAs, bind transcription through to RNA processing, localization and to distinct elements in target RNAs, thereby exerting specifi c decay to the synthesis of proteins and their post-translational and concerted control over posttranscriptional events. In this modifi cations. Regarding the fi rst steps in the control of gene review, we discuss recent reports committed to systematically expression, one of the earliest possibilities for coordination is explore the RNA-protein interaction network and outline some provided by the chromatin structure of the genome. The struc- of the principles and recurring features of RNA regulons: the ture can be separated roughly into heterochromatin, which coordination of functionally related mRNAs through RNA- is transcriptionally silent, and euchromatin, which governs binding proteins or non-coding RNAs, the modular structure access to transcription factors through the density of pack- of its components, and the dynamic rewiring of RNA-protein aged structural proteins, such as the histones. Continuing from interactions upon exposure to internal or external stimuli. We this, the physical linkage of genes allows for co-expression, also summarize evidence for robust combinatorial control exemplifi ed by the homeobox genes, which form a sequential of mRNAs, which could determine the ultimate fate of each cluster on the chromosome to facilitate a developmental cas- mRNA molecule in a cell. Finally, the compilation and inte- cade (3) . Ultimately, the transcription of genes is coordinated gration of global protein-RNA interaction data has yielded by a host of cell and tissue-specifi c transcription factors (TFs) fi rst insights into network structures and provided the hypoth- (e.g., homeobox proteins) that bind to specifi c DNA promoter esis that RNA regulons may, in part, constitute noise ‘ buffers ’ sequences and recruit RNA-polymerases for RNA synthesis. to handle stochasticity in cellular transcription. Hence, TFs generally activate sets of genes coding for pro- teins that are structurally or functionally related. Keywords: gene regulatory networks; non-coding RNA; As cellular mRNA transcript levels are limited indica- post-transcriptional gene regulation; protein-RNA tors of protein abundance (4 – 7) , additional layers of control interaction; RNA-binding protein. must exist to ensure coordinated protein synthesis. Moreover, the presence of the nuclear membrane in eukaryotes, which results in a spatial separation of transcription and translation, a These authors contributed equally to this work. requires structures to coordinate production and distribution 404 J. Imig et al. of the large number of mRNA molecules present in a cell as RBPs (14) . In the worm Caenorhabditis elegans and in ( ∼ 150,000 mRNA molecules in a mammalian cell). Such the fruitfl y Drosophila melanogaster approximately 2 % and post-transcriptional coordination is mediated by a plethora in humans about 5 % of the protein coding genes are anno- of RNA-binding proteins (RBPs) that dynamically associ- tated as ‘ RNA binding ’ (UniProt/ Swissprot release 2012_2). ate with specifi c subpopulations of transcripts. Additionally, However, it is likely that the number of RBPs is even higher RBPs form ribonucleoprotein particles (RNPs) with small in light of the recent discoveries of many potentially novel non-coding RNAs (ncRNAs), such as microRNAs (miR- RBPs (15, 16) . Furthermore, several of the RNA-binding NAs), that participate in complementary binding to mRNA domains, such as the RRM, underwent drastic amplifi cation targets and repress translation or promote decay of their target during animal evolution (12) , in parallel with the evolution of mRNAs. Hundreds of RBPs and ncRNAs are expressed in highly specifi c post-transcriptional processes, such as alterna- eukaryotes – most of them with unknown functions – suggest- tive splicing, allowing an increased genetic diversity from a ing an elaborate system for post-transcriptional control that limited repertoire of genes. This may have consequences for may affect virtually every mRNA in a cell. human disease: many mutations in RBP genes are linked to With the development of genomic tools, it became feasible muscular and neurodegenerative disorders, which parallels to study the extent and logic of post-transcriptional gene regu- rapid evolution of neurological functions in primates (17) ; lation on a global scale. These technologies enabled the com- an increasing number of RBPs are being linked to cancer by prehensive identifi cation of mRNAs specifi cally associated acting as oncogenes or tumor suppressors (18) ; some RBPs with RBPs and miRNAs (see below). They also enabled the coordinate the initiation and resolution of infl ammation (19) . comprehensive measurement of RNA processing events in the Messenger RNAs can also be regulated via direct physi- nucleus (e.g., alternative-splicing and polyadenylation), the cal interactions with ncRNAs. The best-characterized class systematic exploration of mRNA localization, and the global of such RNAs is the large family of microRNAs (miRNAs), determination of mRNA decay and translation rates. In sum- ∼ 22-nucleotide-long RNA molecules that negatively regu- mary, genomics tools have provided important clues about late gene expression in metazoans [reviewed in (20, 21) ]. the architecture of the post-transcriptional regulatory system. MicroRNAs are processed from larger precursors in a series of Importantly – and by analogy with prokaryotic DNA operons – steps, and they are fi nally incorporated into the RNA-induced they showed that groups of mRNAs coding for functionally silencing complex (RISC) – the main component of which related proteins are commonly regulated and/or bound to is a member of the Argonaute (Ago) protein family. ‘ Seed ’ regulatory components, such as RBPs and/or miRNAs. This sequences in the miRNA (typically seven to eight nucleotides supports a model in which functionally related messages are at the 5 ′ -terminus) guide the miRNA-loaded RISC (miRISC) dynamically controlled by trans -acting factors that interact complexes towards partially complementary sequences in via cis -acting elements in the RNA, forming so-called RNA 3 ′ -untranslated regions (3 ′ -UTRs) of target mRNAs and regulons (8, 9) . thereby inhibit translation or promote mRNA decay. Almost This review summarizes concepts and features of RNA 2000 miRNAs have been discovered in human cells so far regulons and how their effectors are controlled. We mainly (22) , with an increasing number of them linked to important focus on cytoplasmic events that govern the coordination of the localization, translation, and decay of mRNA molecules. physiological and developmental processes and diseases (23) . We highlight recent studies and observations that support and further extend the RNA regulon model, describing features Ribonomics – global methods for the identifi cation of a highly complex post-transcriptional gene regulatory of RNA-protein
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