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The Arabidopsis Epitranscriptome Available online at www.sciencedirect.com ScienceDirect The Arabidopsis epitranscriptome 1 2 Rupert G Fray and Gordon G Simpson The most prevalent internal modification of plant messenger for Arabidopsis embryogenesis [1], and crucial to proper 6 6 RNAs, N -methyladenosine (m A), was first discovered in the development [2]. Consequently, the control and impact 1970s, then largely forgotten. However, the impact of of an entire layer of gene regulation awaits discovery. modifications to eukaryote mRNA, collectively known as the 6 epitranscriptome, has recently attracted renewed attention. Methylating mRNA m A mRNA methylation is required for normal Arabidopsis The most prevalent internal modification of eukaryotic 6 development and the first methylation maps reveal that mRNA is methylation of adenosine at the N position 6 thousands of Arabidopsis mRNAs are methylated. Arabidopsis (m A). Although first discovered in mammalian [3,4] and is likely to be a model of wide utility in understanding the plant [5,6] mRNAs in the 1970s, it is only recently that 6 biological impacts of the epitranscriptome. We review recent m A has been mapped transcriptome-wide and that func- 6 progress and look ahead with questions awaiting answers to tions for m A have been uncovered [7 ,8 ]. reveal an entire layer of gene regulation that has until recently 6 been overlooked. Mapping m A modifications 6 Base-specific identification of m A is technically chal- Addresses 1 lenging and not yet feasible transcriptome-wide. Instead, School of Biosciences, University of Nottingham, Sutton Bonington Campus, Loughborough, Leicestershire LE12 5RD, UK the current state-of-the-art involves using antibodies that 2 6 Division of Plant Sciences, College of Life Sciences, University of recognize m A to immunoprecipitate and then sequence Dundee, Cell and Molecular Sciences, James Hutton Institute, RNAs carrying this modification in a procedure known as Invergowrie DD2 5DA, Scotland, UK 6 MeRIP-Seq [9]. Because the specificity of anti-m A antibodies is variable, such experiments should ideally Corresponding authors: Fray, Rupert G ([email protected]) and Simpson, Gordon G ([email protected]) be controlled for by sequencing genetic backgrounds defective in mRNA methylation [10 ], and possibly in conjunction with cross-linking of the methylating Current Opinion in Plant Biology 2015, 27:17–21 enzymes to reference the directness of the reactions This review comes from a themed issue on Cell signalling and gene involved. regulation 6 0 Edited by Xiaofeng Cao and Blake C Meyers m A is mostly associated with the 3 end of Arabidopsis mRNA transcripts (within 150 nt of the poly(A) tail) [2]. For a complete overview see the Issue and the Editorial Subsequent MeRIP-Seq transcriptome-wide mapping Available online 3rd June 2015 studies with yeast, human and Arabidopsis mRNA con- http://dx.doi.org/10.1016/j.pbi.2015.05.015 firm this phenomenon, revealing a peak of methylation in 0 # 1369-5266/ 2015 The Authors. Published by Elsevier Ltd. This is an 3 UTRs and over the stop codon [10 ,11,12 ]. A consen- open access article under the CC BY license (http://creativecommons. sus methylation target sequence closely related to that org/licenses/by/4.0/). derived for human data of (G/A)(G/A)ACU, is found in different eukaryotes and is consistent with a previously established methylation motif identified by in vitro en- The Arabidopsis genome: from both sides zyme activity, RNAse fragmentation and labelling stud- now? ies [13], and by direct biochemical mapping of sites in The landmark sequencing of the Arabidopsis thaliana Rous sarcoma virus and bovine prolactin transcripts (Arabidopsis) genome in 2000, still leaves us asking what [14,15]. the genome really encodes? Subsequent sequencing of 0 6 Arabidopsis RNAs reveals alternative transcription start Although enriched in 3 UTRs, m A is found throughout sites, alternative splicing and alternative sites of cleavage mRNAs, including intronic sequences, indicating the and polyadenylation of RNAs transcribed from the same modification may be added co-transcriptionally [16]. It locus. The more we sequence in different genotypes, cell- is not yet known whether nascent transcripts are more types and situations, the more evidence of alternative widely methylated and then subsequently demethylated 0 processing we detect, and the more non-protein-coding in specific regions. In addition to the 3 enrichment, RNAs of unknown function we find. But that’s not all. Arabidopsis MeRIP-Seq data indicates an increased 6 0 Although we have sequenced from both sides now, DNA abundance of m A at the 5 end of some transcripts. 6 and RNA, the modifications of mRNA, known as the However, an association of m A with long exons that epitranscriptome, have been almost completely over- has been found in mammalian mRNA was not reported in looked. Yet we know mRNA methylation is essential the first Arabidopsis MeRIP-Seq data [12 ]. www.sciencedirect.com Current Opinion in Plant Biology 2015, 27:17–21 18 Cell signalling and gene regulation Figure 1 Pre-mRNA processing Nuclear export mRNA stability Interpreters mRNA Localization Translation efficiency YTH Readers 6 7Gppp GGm ACU AAAAAAAAAAAAAA N N N N N MTB? H CH3 Writers ? MTA FIP37 H H AlkB N Erasers ? N N Other Modifications ? N N 7Gppp GGACU AAAAAAAAAAAAAA Current Opinion in Plant Biology 6 The Arabidopsis epitranscriptome. The most prevalent internal modification of eukaryote mRNA is methylation of adenosine at the N position. 6 0 Although m A is found throughout mRNA it is enriched towards the 3 end of Arabidopsis mRNAs. This code is written by a writer complex comprised of MTA, FIP37 and probably other proteins that likely include a protein closely related to MTA called MTB. In humans this modification is apparently reversible through the action of AlkB family proteins. Although related AlkB family proteins exist in Arabidopsis, there is no evidence 6 yet that they are involved in this process. m A is read by YTH domain proteins, but the combination of direct and indirect influences on RNP composition and structure determine mRNA fate. Other modifications to Arabidopsis mRNA likely remain to be discovered. It is clear that mRNA transcribed from thousands of functional methylation complexes [17–19]. MTA and Arabidopsis genes is methylated, but due to the limita- FIP37 are predominantly nuclear localized [1], indicat- 6 tions of MeRIP-Seq, the best peak-calling data corre- ing that m A modification takes place in the nucleus. spond to the most abundant RNA transcripts. Further However, the possibility that some methylation of Arabidopsis MeRIP-Seq studies and alternative valida- mRNA might occur in the cytoplasm cannot be ruled tion approaches will be needed to help clarify the RNA out at this stage. The exact composition of the writer methylome. complexes, their regulation and the degree of conser- vation remains to be determined. It is clear that not 6 Writing m A all mRNAs are methylated and not all potential con- The Arabidopsis enzyme MTA (TAIR: At4g10760) is sensus target sites are methylated either. However, the 6 required for mRNA methylation [1]. Null mutant alleles mechanistic or regulatory basis of m A selectivity is 6 are embryo lethal, indicating that mRNA m A is essential unknown. for plant survival [1]. Expressing MTA under the control 6 of the largely embryo-specific ABI3 promoter rescues Reading and interpreting m A 6 lethality of null mta mutants and the plants go on to m A can directly influence the stability or conformation of 6 complete seed-set [2]. m A levels in these plants are RNA in the absence of RNA binding proteins [20]. In 6 reduced to 5–15% levels of wild-type, confirming the addition, m A can be ‘read’ directly by YTH domain 6 requirement for this enzyme to methylate mRNA m A. containing proteins that bind this modification specifical- ly [21 ]. There are 13 Arabidopsis genes predicted to It seems likely that a conserved complex of proteins encode YTH domain containing proteins, but their func- 6 mediates m A mRNA methylation in different eukar- tions are almost wholly uncharacterized [22,23]. Structur- yotes. MTA interacts with FIP37 in plants [1], and al analyses indicate that a cage of aromatic amino acids in 6 subsequently, the interaction of the human (METTL3 the YTH domain binds m A [24,25]. Notably, the corre- and Wilm’s Tumor Associated Protein, WTAP, respec- sponding aromatic residues are conserved in each pre- tively) and yeast (IME4 and Mum2 respectively) homo- dicted Arabidopsis YTH domain protein, suggesting 6 logs have been shown to be integral to the formation of that they have the potential to bind m A. Transcripts Current Opinion in Plant Biology 2015, 27:17–21 www.sciencedirect.com The Arabidopsis epitranscriptome Fray and Simpson 19 encoding Arabidopsis YTH domain proteins show dis- Interestingly AlkB proteins with a demonstrated prefer- tinct developmental expression patterns and responses to ence for RNA substrates are encoded in some viruses that abiotic and biotic stresses [23]. infect plants [36]. Although these enzymes may function to repair the RNA genomes of these viruses, an untested One Arabidopsis YTH domain protein is relatively well possibility is that they may target host mRNAs during characterised: the Arabidopsis homologue of mRNA infection. The interplay between the epitranscriptome Cleavage and Polyadenylation Specificity Factor 30 and pathogen interactions is unexplored (Figure 1). (CPSF30) [26 ]. It has recently been shown in mammali- 6 an cells that CPSF30 plays a crucial role in cleavage and The dynamic nature of m A methylation 6 polyadenylation because together with WDR33 it appears If m A is regulatory, one might expect it to be dynamic. to be involved in binding to and selecting the poly(A) There is so far insufficient data to know if this is the case 6 signal AAUAAA [27,28].
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