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      Diverse RNA-Binding Proteins Interact with Functionally Related Sets of RNAs, Suggesting an Extensive Regulatory System

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          Abstract

          RNA-binding proteins (RBPs) have roles in the regulation of many post-transcriptional steps in gene expression, but relatively few RBPs have been systematically studied. We searched for the RNA targets of 40 proteins in the yeast Saccharomyces cerevisiae: a selective sample of the approximately 600 annotated and predicted RBPs, as well as several proteins not annotated as RBPs. At least 33 of these 40 proteins, including three of the four proteins that were not previously known or predicted to be RBPs, were reproducibly associated with specific sets of a few to several hundred RNAs. Remarkably, many of the RBPs we studied bound mRNAs whose protein products share identifiable functional or cytotopic features. We identified specific sequences or predicted structures significantly enriched in target mRNAs of 16 RBPs. These potential RNA-recognition elements were diverse in sequence, structure, and location: some were found predominantly in 3′-untranslated regions, others in 5′-untranslated regions, some in coding sequences, and many in two or more of these features. Although this study only examined a small fraction of the universe of yeast RBPs, 70% of the mRNA transcriptome had significant associations with at least one of these RBPs, and on average, each distinct yeast mRNA interacted with three of the RBPs, suggesting the potential for a rich, multidimensional network of regulation. These results strongly suggest that combinatorial binding of RBPs to specific recognition elements in mRNAs is a pervasive mechanism for multi-dimensional regulation of their post-transcriptional fate.

          Author Summary

          Regulation of gene transcription has been extensively studied, but much less is known about how the fates of the resulting mRNA transcripts are regulated. We were intrigued by the fact that while most eukaryotic genomes encode hundreds of RNA-binding proteins (RBPs), the targets and regulatory roles of only a small fraction of these proteins have been characterized. In this study, we systematically identified the RNAs associated with a select sample of 40 of the approximately 600 predicted RBPs in the budding yeast, Saccharomyces cerevisiae. We found that most of these RBPs bound specific sets of mRNAs whose protein products share physiological themes or similar locations within the cell. For 16 of the 40 RBPs, we identified sequence motifs significantly enriched in their RNA targets that presumably mediate recognition of the target by the RBP. The intricate, overlapping patterns of mRNAs associated with RBPs suggest an extensive combinatorial system for post-transcriptional regulation, involving dozens or even hundreds of RBPs. The organization and molecular mechanisms involved in this regulatory system, including how RBP–mRNA interactions are integrated with signal transduction systems and how they affect the fates of their RNA targets, provide abundant opportunities for investigation and discovery.

          Abstract

          A systematic study of the RNA targets of 40 known or predicted RNA-binding proteins in yeast suggests that an extensive system of dozens or hundreds of specific RNA-binding proteins may act to regulate the post-transcriptional fate of most or all RNAs in the yeast cell.

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          Most cited references 142

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          Gene ontology: tool for the unification of biology. The Gene Ontology Consortium.

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            Cluster analysis and display of genome-wide expression patterns.

            A system of cluster analysis for genome-wide expression data from DNA microarray hybridization is described that uses standard statistical algorithms to arrange genes according to similarity in pattern of gene expression. The output is displayed graphically, conveying the clustering and the underlying expression data simultaneously in a form intuitive for biologists. We have found in the budding yeast Saccharomyces cerevisiae that clustering gene expression data groups together efficiently genes of known similar function, and we find a similar tendency in human data. Thus patterns seen in genome-wide expression experiments can be interpreted as indications of the status of cellular processes. Also, coexpression of genes of known function with poorly characterized or novel genes may provide a simple means of gaining leads to the functions of many genes for which information is not available currently.
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              The transcriptional landscape of the yeast genome defined by RNA sequencing.

              The identification of untranslated regions, introns, and coding regions within an organism remains challenging. We developed a quantitative sequencing-based method called RNA-Seq for mapping transcribed regions, in which complementary DNA fragments are subjected to high-throughput sequencing and mapped to the genome. We applied RNA-Seq to generate a high-resolution transcriptome map of the yeast genome and demonstrated that most (74.5%) of the nonrepetitive sequence of the yeast genome is transcribed. We confirmed many known and predicted introns and demonstrated that others are not actively used. Alternative initiation codons and upstream open reading frames also were identified for many yeast genes. We also found unexpected 3'-end heterogeneity and the presence of many overlapping genes. These results indicate that the yeast transcriptome is more complex than previously appreciated.
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                Author and article information

                Journal
                PLoS Biol
                pbio
                plbi
                plosbiol
                PLoS Biology
                Public Library of Science (San Francisco, USA )
                1544-9173
                1545-7885
                October 2008
                28 October 2008
                : 6
                : 10
                Affiliations
                [1 ] Department of Biochemistry, Stanford University School of Medicine, Stanford, California, United States of America
                [2 ] Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, California, United States of America
                [3 ] Department of Genetics, Stanford University School of Medicine, Stanford, California, United States of America
                [4 ] Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, ETH Zurich, Zurich, Switzerland
                Author notes
                * To whom correspondence should be addressed. E-mail: pbrown@ 123456pmgm2.stanford.edu (POB); herschla@ 123456stanford.edu (DH); andre.gerber@ 123456pharma.ethz.ch (AG)
                Article
                08-PLBI-RA-1298R4 plbi-06-10-13
                10.1371/journal.pbio.0060255
                2573929
                18959479
                Copyright: © 2008 Hogan et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                Page count
                Pages: 17
                Categories
                Research Article
                Genetics and Genomics
                Molecular Biology
                Custom metadata
                Hogan DJ, Riordan DP, Gerber AP, Herschlag D, Brown PO (2008) Diverse RNA-binding proteins interact with functionally related sets of RNAs, suggesting an extensive regulatory system. PLoS Biol 6(10): e255. doi: 10.1371/journal.pbio.0060255

                Life sciences

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