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Global Analysis of Ribosome-Associated Noncoding Rnas Unveils New Modes of Translational Regulation

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Global Analysis of Ribosome-Associated Noncoding Rnas Unveils New Modes of Translational Regulation Global analysis of ribosome-associated noncoding RNAs unveils new modes of translational regulation Jérémie Bazina,b,c, Katja Baerenfallerd, Sager J. Gosaie, Brian D. Gregorye, Martin Crespic, and Julia Bailey-Serresa,b,1 aCenter for Plant Cell Biology, University of California, Riverside, CA 92521; bDepartment of Botany and Plant Sciences, University of California, Riverside, CA 92521; cInstitute of Plant Sciences Paris-Saclay (IPS2), CNRS, Institut National de la Recherche Agronomique, Université Paris-Sud, Université Paris-Saclay, 91405 Orsay, France; dDepartment of Biology, Eidgenössiche Technische Hochschule, 8092 Zurich, Switzerland; and eDepartment of Biology, University of Pennsylvania, Philadelphia, PA 19104 Contributed by Julia Bailey-Serres, October 3, 2017 (sent for review May 22, 2017; reviewed by Javier Paz-Ares and Shu-Hsing Wu) Eukaryotic transcriptomes contain a major non–protein-coding com- mice (72%), humans (61–72%)] (6). A survey of A. thaliana ponent that includes precursors of small RNAs as well as long non- transcriptomes from multiple tissues and growth conditions iden- coding RNA (lncRNAs). Here, we utilized the mapping of ribosome tified 37,238 sense–antisense transcript pairs, corresponding to footprints on RNAs to explore translational regulation of coding and 70% of annotated mRNAs (7). Many NATs are detectable only in noncoding RNAs in roots of Arabidopsis thaliana shifted from re- mutants defective in mRNA degradation (8), indicating that their plete to deficient phosphorous (Pi) nutrition. Homodirectional abundance is tightly regulated. changes in steady-state mRNA abundance and translation were ob- lncRNAs can function in the nucleus or cytoplasm. Nuclei of served for all but 265 annotated protein-coding genes. Of the trans- Arabidopsis seedlings accumulate over 200 lncRNAs, including lationally regulated mRNAs, 30% had one or more upstream ORF over 30 that are protein-bound and evolutionarily conserved (9). (uORF) that influenced the number of ribosomes on the principal One of these is AUXIN REGULATED PROMOTER LOOP RNA protein-coding region. Nearly one-half of the 2,382 lncRNAs de- (APOLO), which controls a chromatin loop and DNA methylation tected had ribosome footprints, including 56 with significantly al- at the neighboring PINOID locus, thereby modulating its tran- tered translation under Pi-limited nutrition. The prediction of scription (10). The cis-NATs collectively named COOLAIR are translated small ORFs (sORFs) by quantitation of translation termi- generated from the opposite strand of the FLOWERING LOCUS nation and peptidic analysis identified lncRNAs that produce pep- C (FLC)ofA. thaliana and its relative A. alpina (8). COOLAIR tides, including several deeply evolutionarily conserved and significantly Pi-regulated lncRNAs. Furthermore, we discovered that RNAs mediate deposition of the repressive chromatin mark tri- natural antisense transcripts (NATs) frequently have actively trans- methylated histone H3 Lys27 at FLC to control the process of lated sORFs, including five with low-Pi up-regulation that correlated vernalization (2). Thus, nuclear lncRNAs can determine epige- with enhanced translation of the sense protein-coding mRNA. The netic or transcriptional regulation in plants. data also confirmed translation of miRNA target mimics and Cytoplasmic lncRNAs serve diverse roles in the regulation of lncRNAs that produce trans-acting or phased small-interfering RNA mRNA stability and translation. For example, a mammalian (tasiRNA/phasiRNAs). Mutational analyses of the positionally con- mRNA with an ALU motif in its 3′-untranslated region (UTR) is served sORF of TAS3a linked its translation with tasiRNA biogenesis. recognized by a lncRNA that facilitates association of an RNA Altogether, this systematic analysis of ribosome-associated mRNAs and lncRNAs demonstrates that nutrient availability and transla- Significance tional regulation controls protein and small peptide-encoding mRNAs as well as a diverse cadre of regulatory RNAs. Noncoding RNAs are an underexplored reservoir of regulatory molecules in eukaryotes. We analyzed the environmental re- long noncoding RNA | ribosome footprint profiling | small peptides | sponse of roots to phosphorus (Pi) nutrition to understand how a phosphate deficiency | Arabidopsis thaliana change in availability of an essential element is managed. Pi availability influenced translational regulation mediated by small large fraction of the transcripts produced from the nuclear upstream ORFs on protein-coding mRNAs. Discovery, classifica- Agenomes of eukaryotes do not code for proteins (1). In the tion, and evaluation of long noncoding RNAs (lncRNAs) associated case of the model flowering plant Arabidopsis thaliana, an esti- with translating ribosomes uncovered diverse new examples of mated 80–90% of the genome is transcribed at some point translational regulation. These included Pi-regulated small peptide during development (2) with an estimated 38% encoding pro- synthesis, ribosome-coupled phased small interfering RNA pro- teins of ≥100 aa. The other transcripts encode non–protein- duction, and the translational regulation of natural antisense coding housekeeping RNAs (tRNAs, ribosomal RNAs, small RNAs and other regulatory RNAs. This study demonstrates that nuclear and nucleolar RNAs), regulatory RNAs involved in gene translational control contributes to the stability and activity of silencing [microRNAs (miRNAs), small interfering RNAs (siR- regulatory RNAs, providing an avenue for manipulation of traits. NAs) (3)], and the diverse cohort called long noncoding RNAs (lncRNAs). lncRNAs are subclassified according to their site of Author contributions: J.B., S.J.G., B.D.G., M.C., and J.B.-S. designed research; J.B., K.B., and origin, orientation relative to neighboring genes, cellular com- S.J.G. performed research; J.B. and M.C. contributed new reagents/analytic tools; J.B., K.B., and J.B.-S. analyzed data; and J.B., K.B., M.C., and J.B.-S. wrote the paper. partmentation, and function (reviewed for plants by ref. 4). Reviewers: J.P.-A., Spanish National Center of Biotechnology; and S.-H.W., These include lncRNAs transcribed from intergenic or intronic Academia Sinica. regions (lincRNAs), natural antisense transcripts (NATs) com- The authors declare no conflict of interest. plementary to protein-coding transcripts, and precursors of small This open access article is distributed under Creative Commons Attribution-NonCommercial- RNAs (sRNAs) including trans-acting phased small interfering NoDerivatives License 4.0 (CC BY-NC-ND). RNAs (tasiRNA/phasiRNA) and microRNAs (miRNA). NATs Data deposition: The data reported in this paper have been deposited in the Gene Ex- originate from the reverse strand of sense (protein) coding regions pression Omnibus (GEO) database, https://www.ncbi.nlm.nih.gov/geo (accession no. (cis-NATs) or from distinct genomic loci (trans-NATs) and are GSE98610). often associated with regulation of development (5). There is a 1To whom correspondence should be addressed. Email: [email protected]. profusion of NATs of cognate protein-coding genes in eukaryotes This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. [Saccharomyces cerevisiae (27%), Drosophila melanogaster (17%), 1073/pnas.1708433114/-/DCSupplemental. E10018–E10027 | PNAS | Published online October 30, 2017 www.pnas.org/cgi/doi/10.1073/pnas.1708433114 Downloaded by guest on October 1, 2021 binding protein that activates mRNA decay when the transcript is known lncRNAs such as endogenous miRNA target mimics and PNAS PLUS ribosome-associated (11). Some plant cytoplasmic lncRNAs par- tasiRNAs/phasiRNAs. We also demonstrate that translation of the ticipate in molecular mimicry that controls the activity of miRNAs TAS3a sORF enhances tasiRNA production. (12, 13). For example, Arabidopsis INDUCED BY PHOSPHATE STARVATION 1 and 2 (IPS1, IPS2/AT4) and their orthologs in Results and Discussion other species are strongly induced in roots deficient in inorganic Phosphate Deficiency Impacts the Translational Regulation of a Subset − phosphate (H2PO4 ;Pi)(4,12).IPS1/2 bind miR399 but are a poor of mRNAs. A comparative transcriptome and ribosome-footprinting substrate for miRNA-mediated cleavage. It is the elevation of these study was performed on the complete root system of seedlings endogenous miRNA target mimics (eTMs) under Pi deficiency initiated on replete Pi (500 μMPi,+P) medium for 7 d and then that fine-tunes regulation of the true miR399 target PHOSPHATE transferred to replete or deficient (12.5 μMPi,−P) medium for an 2 (PHO2). This gene encodes a ubiquitin-conjugating enzyme additional 7 d. The long-term low-Pi treatment triggered the E2 that promotes turnover of Pi transporters. IPS1/2 up-regulation typical adaptative response of the Arabidopsis root system with ultimately reduces PHO1 (14) and related transporters to maintain attenuated growth of the primary root and stimulation of the correct Pi homeostasis (15). Beyond these, the regulation and emergence and elongation of lateral roots (Fig. 1A), a plasticity in function of the vast majority of cytoplasmic lncRNAs in plants development that enhances capture of mineral reserves in the remain uncharacterized (4, 7, 16, 17). rhizosphere near the soil surface (33). Root tissue was used to + The development of high-throughput ribosome profiling (ribo- isolate total cellular poly(A) mRNA as well as to determine the seq) methods that map the position of individual 80S ribosome position of individual
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