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Evolutionary Conservation and Diversification of Puf RNA Binding Proteins and Their mRNA Targets

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      Abstract

      Reprogramming of a gene’s expression pattern by acquisition and loss of sequences recognized by specific regulatory RNA binding proteins may be a major mechanism in the evolution of biological regulatory programs. We identified that RNA targets of Puf3 orthologs have been conserved over 100–500 million years of evolution in five eukaryotic lineages. Focusing on Puf proteins and their targets across 80 fungi, we constructed a parsimonious model for their evolutionary history. This model entails extensive and coordinated changes in the Puf targets as well as changes in the number of Puf genes and alterations of RNA binding specificity including that: 1) Binding of Puf3 to more than 200 RNAs whose protein products are predominantly involved in the production and organization of mitochondrial complexes predates the origin of budding yeasts and filamentous fungi and was maintained for 500 million years, throughout the evolution of budding yeast. 2) In filamentous fungi, remarkably, more than 150 of the ancestral Puf3 targets were gained by Puf4, with one lineage maintaining both Puf3 and Puf4 as regulators and a sister lineage losing Puf3 as a regulator of these RNAs. The decrease in gene expression of these mRNAs upon deletion of Puf4 in filamentous fungi ( N. crassa) in contrast to the increase upon Puf3 deletion in budding yeast ( S. cerevisiae) suggests that the output of the RNA regulatory network is different with Puf4 in filamentous fungi than with Puf3 in budding yeast. 3) The coregulated Puf4 target set in filamentous fungi expanded to include mitochondrial genes involved in the tricarboxylic acid (TCA) cycle and other nuclear-encoded RNAs with mitochondrial function not bound by Puf3 in budding yeast, observations that provide additional evidence for substantial rewiring of post-transcriptional regulation. 4) Puf3 also expanded and diversified its targets in filamentous fungi, gaining interactions with the mRNAs encoding the mitochondrial electron transport chain (ETC) complex I as well as hundreds of other mRNAs with nonmitochondrial functions. The many concerted and conserved changes in the RNA targets of Puf proteins strongly support an extensive role of RNA binding proteins in coordinating gene expression, as originally proposed by Keene. Rewiring of Puf-coordinated mRNA targets and transcriptional control of the same genes occurred at different points in evolution, suggesting that there have been distinct adaptations via RNA binding proteins and transcription factors. The changes in Puf targets and in the Puf proteins indicate an integral involvement of RNA binding proteins and their RNA targets in the adaptation, reprogramming, and function of gene expression.

      Abstract

      A map of the evolutionary history of Puf proteins and their RNA targets shows that reprogramming of global gene expression programs via adaptive mutations that affect protein-RNA interactions is an important source of biological diversity.

      Author Summary

      We set out to trace the evolutionary history of an RNA binding protein and how its interactions with targets change over evolution. Identifying this natural history is a step toward understanding the critical differences between organisms and how gene expression programs are rewired during evolution. Using bioinformatics and experimental approaches, we broadly surveyed the evolution of binding targets of a particular family of RNA binding proteins—the Puf proteins, whose protein sequences and target RNA sequences are relatively well-characterized—across 99 eukaryotic species. We found five groups of species in which targets have been conserved for at least 100 million years and then took advantage of genome sequences from a large number of fungal species to deeply investigate the conservation and changes in Puf proteins and their RNA targets. Our analyses identified multiple and extensive reconfigurations during the natural history of fungi and suggest that RNA binding proteins and their RNA targets are profoundly involved in evolutionary reprogramming of gene expression and help define distinct programs unique to each organism. Continuing to uncover the natural history of RNA binding proteins and their interactions will provide a unique window into the gene expression programs of present day species and point to new ways to engineer gene expression programs.

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      Most cited references 153

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           Robert Edgar (2004)
          We describe MUSCLE, a new computer program for creating multiple alignments of protein sequences. Elements of the algorithm include fast distance estimation using kmer counting, progressive alignment using a new profile function we call the log-expectation score, and refinement using tree-dependent restricted partitioning. The speed and accuracy of MUSCLE are compared with T-Coffee, MAFFT and CLUSTALW on four test sets of reference alignments: BAliBASE, SABmark, SMART and a new benchmark, PREFAB. MUSCLE achieves the highest, or joint highest, rank in accuracy on each of these sets. Without refinement, MUSCLE achieves average accuracy statistically indistinguishable from T-Coffee and MAFFT, and is the fastest of the tested methods for large numbers of sequences, aligning 5000 sequences of average length 350 in 7 min on a current desktop computer. The MUSCLE program, source code and PREFAB test data are freely available at http://www.drive5. com/muscle.
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            Author and article information

            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 Chemistry, Stanford University, Stanford, California, United States of America
            [4 ]Department of Chemical Engineering, Stanford University, Stanford, California, United States of America
            [5 ]ChEM-H Institute, Stanford University, Stanford, California, United States of America
            Case Western Reserve University, UNITED STATES
            Author notes

            The authors have declared that no competing interests exist.

            Conceived and designed the experiments: GJH POB DH. Performed the experiments: GJH. Analyzed the data: GJH. Contributed reagents/materials/analysis tools: GJH POB DH. Wrote the paper: GJH POB DH.

            [¤a]

            Current address: Counsyl, South San Francisco, California, United States of America

            [¤b]

            Current address: Impossible Foods, Redwood City, California, United States of America

            Contributors
            Role: Academic Editor
            Journal
            PLoS Biol
            PLoS Biol
            plos
            plosbiol
            PLoS Biology
            Public Library of Science (San Francisco, CA USA )
            1544-9173
            1545-7885
            20 November 2015
            November 2015
            : 13
            : 11
            26587879 4654594 10.1371/journal.pbio.1002307 PBIOLOGY-D-15-00981

            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

            Counts
            Figures: 8, Tables: 1, Pages: 47
            Product
            Funding
            This work was supported by grants from the National Institutes of Health (NIH RO1 CA77097 to P.O.B. and PO1 066275 to DH). POB is an investigator for the Howard Hughes Medical Institute. GJH was supported in part by a Burt and Deedee McMurtry Stanford Graduate Fellowship and by the Howard Hughes Medical Institute. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
            Categories
            Research Article
            Custom metadata
            All relevant data are within the paper and its Supporting Information files. Microarray data are also available from Gene Expression Omnibus (GEO) under the accession number GSE50997.

            Life sciences

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