Alternative Splicing and Cross-Talk with Light Signaling

Alternative Splicing and Cross-Talk with Light Signaling Abstract Alternative splicing (AS) is the main source of proteome diversity that in large part contributes to the complexity of eukaryotes. Recent global analysis of AS with RNA sequencing has revealed that AS is prevalent in plants, particularly when responding to environmental changes. Light is one of the most important environmental factors for plant growth and development. To optimize light absorption, plants evolve complex photoreceptors and signaling systems to regulate gene expression and biological processes in the cell. Genome-wide analyses have shown that light induces intensive AS in plants. However, the biochemical mechanisms of light regulating AS remain poorly understood. In this review, we aim to discuss recent progress in investigating the functions of AS, discovery of cross-talk between AS and light signaling, and the potential mechanism of light-regulated AS. Understanding how light signaling regulates the efficiency of AS and the biological significance of light-regulated AS in plant systems will provide new insights into the adaptation of plants to their environment and, ultimately, crop improvement. Introduction Alternative splicing (AS) is a widespread mechanism in eukaryotes in which two or more mRNAs are generated from the same precursor mRNA (pre-mRNA) by the use of different splice sites. AS adds a new level of complexity to the transcriptome and is still an underexplored field in plant research. Multicellular eukaryotes have similar gene numbers but with higher complexity compared with single-cellular eukaryotes which can be explained at least in part by the diversity of RNA transcripts from AS. The development of next-generation sequencing (NGS) has provided the opportunity to reveal transcriptome patterns in nucleotide resolution. NGS has shown that almost half of the genes in plants are alternatively spliced (Filichkin et al. 2010, Guo et al. 2010, Zenoni et al. 2010, Zhang et al. 2010, Marquez et al. 2012, Wu et al. 2014). The findings strongly indicate that intensive AS events occur in plant systems to produce a tremendous amount of mRNA and protein isoforms. This function probably plays an important role under changing environments because regulation at the post-transcriptional level allows for immediate responses to dynamic conditions. The importance of AS may be underestimated. Whether AS affects plant growth and development in response to environments is not clearly addressed. How transcriptome and proteome alteration due to AS contributes to biological processes in plants is still little elucidated. As sessile organisms, plants need constantly to adapt to fluctuating environmental conditions. Plants cope with environmental changes by reorganizing their metabolism and gene expression, reaching a new balance among growth, development and survival. Light, one of the most important environmental factors, provides the energy source for plant growth and development. To optimize light absorption, plants evolve complex sensing and signaling systems to regulate gene expression and biological processes in the cell. Photoreceptors, including mainly phytochromes (red and far-red light), cryptochromes (blue light), phototropins (blue light) and UVR8 (UV-B light), sense a different quality (wavelength), quantity (intensity) and direction of light to regulate photomorphological responses throughout the life cycle of plants. Accumulating data suggest that light regulation can occur at different stages of gene expression to control the abundance of functional gene products (see review in Wu 2014). Chromatin modification has been found to be tightly regulated by light (Guo et al. 2008, Fisher and Franklin 2011, Li et al. 2012). Several light signaling components were proposed to function in chromatin regulation (Schroeder et al. 2002). Light-regulated gene expression largely relies on the actions of light signaling transcription factors (Casal and Yanovsky 2005, Jenkins 2009, Chen and Chory 2011, Leivar and Quail 2011). Light also regulates gene expression via translational control. A global survey of transcripts under translational regulation during photomorphogenesis in Arabidopsis has been reported (Liu et al. 2012). Furthermore, light post-translationally controls the abundance of key regulators by ubiquitin-dependent protein degradation (Wei and Deng 2003, Lau and Deng 2012). Although light regulation is found in almost every stage of gene expression, whether light regulates pre-mRNA splicing is still unclear. By taking advantage of NGS and bioinformatics, several groups have observed global changes in AS patterns in response to light in plants (Shikata et al. 2014, Wu et al. 2014, Hartmann et al. 2016, Mancini et al. 2016). The data indicate that light regulates AS to alter the transcriptome globally. Further studies also showed that photoreceptors, splicing regulators and spliceosomal components participate in the light-dependent regulatory process (Shikata et al. 2012, Xin et al. 2017). This review focuses on the function and molecular mechanism of AS in response to light. Constitutive Splicing Versus AS A single mature mRNA can be produced by constitutive splicing from one set of splice sites on the pre-mRNA. Selection of the splice site is determined by cis-acting elements on pre-mRNA that contain exon splicing enhancers/silencers and intron splicing enhancers/silencers, as well as trans-acting regulators that include serine/arginine-rich (SR) proteins and heterogeneous nuclear ribonucleoproteins (hnRNPs) (Fig. 1A). SR proteins and hnRNPs recruited by regulatory cis-elements on pre-mRNA activate or suppress the selection of splice sites and assembly of spliceosomes, large RNP complexes composed of cis-acting elements of pre-mRNA, small nuclear RNPs (snRNPs) and non-snRNP splicing factors (Sharp 1994, Reddy 2001, Zhou et al. 2002). The primary step of spliceosome assembly is the 5' splice site recognition by the U1 snRNP and 3' splice site recognition by the U2 auxillary factors (U2AFs) and U2 snRNP (Fig. 1A). With the stepwise assembly of U4, U5 and U6 snRNPs, and disassembly of U1 and U4 snRNPs, the active spliceosome is formed to catalyze intron cleavage and exon ligation (see reviews by Will and Luhrmann 2011, Hoskins and Moore 2012, Lee and Rio 2015). Fig. 1 View largeDownload slide Regulation and types of alternative splicing (AS). (A) Spliceosome assembly is determined by the cis-acting elements exonic/intronic splicing enhancer (ESE/ISE, colored in green) and exonic/intronic splicing silencer (ESS/ISS, colored in red), together with trans-acting regulators serine/arginine-rich proteins (SR proteins) and heterogeneous nuclear ribonucleoproteins (hnRNPs). Splicing regulators recruited by regulatory cis-elements on pre-mRNA define exon–intron junctions by interacting with U1 or U2 small nuclear RNPs (U1 or U2 snRNPs). (B) Different types of AS events, including exon skipping/inclusion (ES/EI), intron retention (IR) and alternative donor (AltD) and acceptor sites (AltA). Solid line, constitutive splicing (CS); dashed line, AS. Fig. 1 View largeDownload slide Regulation and types of alternative splicing (AS). (A) Spliceosome assembly is determined by the cis-acting elements exonic/intronic splicing enhancer (ESE/ISE, colored in green) and exonic/intronic splicing silencer (ESS/ISS, colored in red), together with trans-acting regulators serine/arginine-rich proteins (SR proteins) and heterogeneous nuclear ribonucleoproteins (hnRNPs). Splicing regulators recruited by regulatory cis-elements on pre-mRNA define exon–intron junctions by interacting with U1 or U2 small nuclear RNPs (U1 or U2 snRNPs). (B) Different types of AS events, including exon skipping/inclusion (ES/EI), intron retention (IR) and alternative donor (AltD) and acceptor sites (AltA). Solid line, constitutive splicing (CS); dashed line, AS. There are four basic types of AS events commonly observed. Elimination of splice site selection leads to intron retention (IR) or exon skipping (ES). Selection of distinct splice sites generates alternative 5' (donor) or 3' (acceptor) splice sites (AltD or AltA) (Fig. 1B) (see reviews in Reddy 2007, Syed et al. 2012). AS events could also simultaneously occur on a single pre-mRNA to produce more diverse transcripts from the same gene. Alternatively spliced transcripts were found early in expressed sequence tags (Iida et al. 2004, Campbell et al. 2006, Wang and Brendel 2006a, Barbazuk et al. 2008). With recent emerging NGS techniques, mRNA sequencing (RNA-seq) has quickly become widely used to identify AS events with high resolution. Over the past decade, the number of alternatively spliced genes identified has increased significantly. In Arabidopsis, >60% of intron-containing genes are reported to be alternatively spliced (Filichkin et al. 2010, Marquez et al. 2012). Analyses in other plant species provided similar results (Guo et al. 2010, Zenoni et al. 2010, Zhang et al. 2010, Wu et al. 2014). IR is the most predominant AS form in plants, whereas ES is prevalent in mammalian cells, which suggests differences in regulation of AS in animals and plants. Impact of AS in Plants AS events bring a different functional meaning to gene products. In terms of IR, most IR events generate unproductive transcripts that contain a premature termination codon in the retained intron or the downstream coding region and are potentially subjected to the nonsense-mediated mRNA decay (NMD) pathway (Kalyna et al. 2012). AS-coupled NMD is an important mechanism to regulate the level of functional transcripts (Reddy et al. 2013, Hamid and Makeyev 2014, Filichkin et al. 2015), which could be essential for plants to respond rapidly to fluctuating environmental conditions. AS events also cause loss or gain of function in protein products, such as producing proteins with or without additional functional domains. These domain-containing or domain-less proteins might have changed protein properties such as subcellular localization, stability, activity or protein interaction that may regulate the activities of full-length proteins. Some gene transcripts are alternatively spliced during environmental changes. For example, light promotes selection of an alternative 5' splice site within intron 12 of HYDROXYPYRUVATE REDUCTASE (HPR) transcripts in pumpkin (Mano et al. 2000). The HPR mRNA isoform induced under light conditions encodes a truncated protein localized in the cytosol because of loss of the peroxisomal targeting sequence at its C-terminus. Light also promotes AltD and IR of SPA1-RELATED 3 (SPA3) transcripts (Shikata et al. 2014). Alternatively spliced isoforms of SPA3 lacking part of the WD-40 repeat domains have a dominant-negative effect to the formation of the endogenous CONSTITUTIVE PHOTOMORPHOGENIC 1 (COP1)–SPA3 complex in ubiquitin-dependent protein degradation. Overexpressing the alternatively spliced isoforms of light signaling factors COP1 and PHYTOCHROME INTERACTING FACTOR 6 in Arabidopsis also has dominant-negative effects in photomorphological control (Zhou et al. 1998, Penfield et al. 2010). AS is particularly rich in gene transcripts involved in flowering time control (Terzi and Simpson 2008). For example, FCA encodes a plant-specific RNA-binding protein that functions in the autonomous pathway to prevent the accumulation of FLOWERING LOCUS C, the potent repressor of flowering (Macknight et al. 1997). Arabidopsis FCA produces several AS isoforms mainly caused by AS at intron 3 (Quesada et al. 2003). This AS pattern of FCA is conserved among plant species (Lee et al. 2005). Regulated expression of splicing variants of flowering-related genes may affect flowering time control. Mutations in pre-mRNA splicing-related genes also led to misregulation of flowering time (Terzi and Simpson 2008). Deficiency in the PRE-mRNA PROCESSING FACTOR 39, a component of U1 snRNP that functions in recruiting U1 snRNP to the 5' splice site to initiate spliceosome assembly, delays flowering in Arabidopsis (Lockhart and Rymond 1994, Wang et al. 2007). Mutation, knockdown or overexpression of other splicing factors such as SR30 (a SR protein), U2AF35 (for U2 snRNP assembly), EARLY FLOWERING 5 (interacts with U5 snRNP) and ENHANCED SILENCING PHENOTYPE 5 (a DEAH RNA helicase) all affect flowering time (Lopato et al. 1999, Noh et al. 2004, Herr et al. 2006, Wang and Brendel 2006b). These findings clearly reveal the tight relationship between regulation of pre-mRNA splicing and flowering time control. Because flowering induction in plants largely depends on environmental cues such as day length, light quality and quantity, and temperature, flowering time control mediated by environmental factors may be regulated by AS. AS patterns are diversified by combinations of regulatory cis-elements and splicing factors, and differential expression and post-translational modification of splicing factors in different cell types, tissues, developmental stages and environmental conditions, which tremendously increases transcriptome complexity and proteome diversity. With more global analyses identifying cell-, tissue- and condition-specific AS in plants, the functional roles of AS in plants for growth and developmental control as well as the response to environmental changes can be further clarified. Genome-Wide Analyses of AS in Response to Light In plants, many gene transcripts undergo AS in response to abiotic and biotic stresses (see reviews by Mastrangelo et al. 2012, Staiger and Brown 2013). Recently, an increasing number of transcriptome-wide studies based on RNA-seq provided evidence that AS globally responds to light in plants (Shikata et al. 2014, Wu et al. 2014, Hartmann et al. 2016, Mancini et al. 2016). RNA-seq in Arabidopsis showed that 1,505 genes (6.9% of Arabidopsis genes) undergo changes in the AS level of their transcripts within 1 h of exposure to red light (Shikata et al. 2014). Regulation of these gene transcripts also depends on phytochromes. In the moss Physcomitrella patens, 8.4% and 8.9% of AS events rapidly respond to red and blue light, respectively (Wu et al. 2014). Responsiveness of these light-dependent AS events is reduced in phytochrome-deficient and -knockout mutants, which suggests that phytochromes participate in regulating AS upon red light irradiation (Wu et al. 2014). The occurrence of light-regulated AS in Physcomitrella is comparable with that in flowering plants and reveals its importance during land colonization of aquatic photosynthetic organisms. Findings from both Arabidopsis and Physcomitrella suggest that photoreceptors, at least phytochromes, primarily participate in regulating AS and that this mechanism is conserved in land plants (Fig. 2A). Fig. 2 View largeDownload slide Potential mechanism of light-regulated AS. Four models are proposed in this review. (A) Phytochromes (Pfrs) activated by light interact with splicing factors (RRC1 and SFPS) to regulate AS. Other splicing factors (SFs) also potentially participate in the regulation. (B) Light-induced energy and retrograde signaling from plastids regulates AS via AS of RS31 or other SF genes. (C and D) Two models, the kinetic-coupling and chromatin-adaptor models, are proposed to explain the potential mechanisms. Based on the kinetic-coupling model, chromatin accessibility caused by the light-altered chromatin landscape affect the speed of transcription, which further regulates AS. Fast transcription elongation causes skipping of splice sites. Slow elongation of transcription allows recognition of weak splice sites. In contrast, the chromatin-adaptor model suggests that the light-altered chromatin mark serves as an anchor for histone adaptor binding, which further recruits splicing factors to regulate AS. Fig. 2 View largeDownload slide Potential mechanism of light-regulated AS. Four models are proposed in this review. (A) Phytochromes (Pfrs) activated by light interact with splicing factors (RRC1 and SFPS) to regulate AS. Other splicing factors (SFs) also potentially participate in the regulation. (B) Light-induced energy and retrograde signaling from plastids regulates AS via AS of RS31 or other SF genes. (C and D) Two models, the kinetic-coupling and chromatin-adaptor models, are proposed to explain the potential mechanisms. Based on the kinetic-coupling model, chromatin accessibility caused by the light-altered chromatin landscape affect the speed of transcription, which further regulates AS. Fast transcription elongation causes skipping of splice sites. Slow elongation of transcription allows recognition of weak splice sites. In contrast, the chromatin-adaptor model suggests that the light-altered chromatin mark serves as an anchor for histone adaptor binding, which further recruits splicing factors to regulate AS. Besides photoreceptor-mediated regulation of AS, other light-triggered signaling pathways may modulate the global pattern of AS (Fig. 2B) (Hartmann et al. 2016, Mancini et al. 2016). Hartmann et al. showed the differential expression of several hundred AS events in etiolated Arabidopsis seedlings undergoing photomorphogenesis upon blue, red or white light irradiation (Hartmann et al. 2016). By characterizing representative AS events, the authors suggested that photoreceptors are involved in only monochromatic but not white light-mediated regulation of AS. Furthermore, they demonstrated that exogenous sugar supply produced similar AS changes to light exposure, which suggests that energy availability plays a role in controlling AS in plants. Plastid to nucleus signaling has also been suggested to regulate AS (Petrillo et al. 2014, Mancini et al. 2016). RNA-seq analysis of Arabidopsis seedlings showed that treatment with an acute light pulse in the middle of the night affected the AS events of 382 genes (Mancini et al. 2016). Characterization of the splicing pattern of splicing factor gene transcripts indicated that AS was not impaired in a quintuple phytochrome mutant, which provides evidence of photoreceptor-independent control of AS in plants (Mancini et al. 2016). This result echoes an earlier study showing a retrograde signal also regulates AS of an SR protein gene transcript in the light response (Petrillo et al. 2014). Although the mechanism of energy and plastid to nucleus signaling is not clear, these results expand the view of light-mediated regulation for AS. In summary, photoreceptor, plastid and energy signaling for splicing regulation can be present simultaneously in plant cells, or occur in different cell types, tissues and developmental stages. These pathways can co-exist to provide multilayer regulation for gene expression. Potential Mechanism of Light-Regulated AS Many gene transcripts undergo AS from dark to light within 1 h, which suggests that light-regulated AS is a rapid response (Shikata et al. 2014, Wu et al. 2014). Two forward genetic studies revealed that phytochromes directly affect pre-mRNA splicing by modulating splicing regulators (Fig. 2A) (Shikata et al. 2012, Xin et al. 2017). Two mutants, reduced red-light response in cry1cry2 background 1 (rrc1) and splicing factor for phytochrome signaling (sfps), were isolated by checking for photomorphogenic defects of Arabidopsis seedlings under red light (Shikata et al. 2012, Xin et al. 2017). Both RRC1 and SFPS encode splicing regulators and form speckles in the nucleus. RRC1 is an ortholog of human SR-like protein SR140 and contains an N-terminal RNA recognition motif (RRM) and a C-terminal arginine/serine-rich (RS) domain. The rrc1 mutant lacking the RS domain shows aberrant AS of several SR protein gene transcripts (SR34, SR34b, RS31, RS31a and RS40) (Shikata et al. 2012). Since the phytochrome B (phyB)-deficient mutant also showed aberrant in red light-dependent AS of RS31 and SR34b transcripts, it is likely that RRC1 regulates AS in a phyB-dependent manner. SFPS encodes an ortholog of human SR-like SPF45 that contains a conserved SF45 motif, a glycine-rich motif and an RRM at its C-terminus. Defects in SFPS alter global AS patterns (Xin et al. 2017). Similar to RRC1, SFPS also regulates AS of several SR genes. SFPS was shown to associate with phytochromes under red light, therefore phytochromes might regulate AS directly. The modulation of AS might be via U2 snRNP because both human SR140 and SPF45 are U2 snRNP-associated proteins (Lallena et al. 2002, Will et al. 2002). Details of the regulatory mechanism for RRC1 and SFPS need further study. Emerging evidence revealed a cross-talk among multiple layers of gene expression. In yeast and mammalian cells, pre-mRNA splicing occurs co-transcriptionally (see reviews by Luco et al. 2011, Herzel et al. 2017). The co-transcriptional splicing is regulated by chromatin landscapes, such as DNA methylation and histone modifications. Two models, the kinetic-coupling and chromatin-adaptor models, are proposed to explain the relationship between chromatin landscapes and AS (Fig. 2C, D) (Luco et al. 2011). In the kinetic-coupling model, chromatin landscapes affect the transcription elongation rate, which further regulates AS. For example, the relationship between IR and chromatin accessibility was explored recently in plants (Ullah et al. 2018). IR is enriched in DNase I-hypersensitive sites, which indicates that IR occurs at DNA opening. Increasing chromatin accessibility allows for fast elongation and promotes splice site skipping (Ullah et al. 2018). In the chromatin-adaptor model, histone modifications serve as anchors for adaptors to recruit splicing regulators (Luco et al. 2010). An example is the recent report on the link between histone modification and temperature-induced AS found in Arabidopsis (Pajoro et al. 2017). Histone H3 Lys36 tri-methylation contributes to differential AS in response to temperature elevation and serves as an anchor for binding a chromatin adaptor, MORF RELATED GENE (MRG). MRG possibly recruits splicing regulators to regulate AS (Pajoro et al. 2017). Although evidence is still lacking to support a co-relationship between light-mediated AS and histone modification, several studies investigating histone modification under different light conditions have unveiled this possibility (Guo et al. 2008, Fisher and Franklin 2011, Li et al. 2012). Besides primary regulation, which directly modulates splicing activities, light-induced transcription and AS of splicing regulator genes affect the expression and functions of splicing regulators. For example, Shikata et al. (2014) showed that seven SR protein genes, i.e. RS31, RS40, RS41, RSZ33, RSZ34, SR34a and SR34b, in Arabidopsis undergo AS in response to light. The AS of these SR protein genes may affect the expression and property of SR proteins that further adjust the transcriptome in the cell. Light-regulated transcription and AS could occur in different cell types, tissues, developmental stages and environmental conditions to affect differentially the abundance of transcripts of splicing regulator genes. Diversified expression of splicing regulators may further alter AS in different cells or under different conditions. These changes have indirect control and thus increase the complexity of the resulting transcriptome. Challenges and Perspectives With the development of NGS, AS in plants has been extensively investigated in recent years. The number of genes with AS that have been identified is growing substantially and is expected to increase with deeper and broader sequencing in different cells, tissues, developmental stages and environmental conditions. RNA-seq of time courses of plant response to environmental changes can be further used to monitor the dynamic changes of AS. AS is now known to be regulated in response to different environmental signals. In terms of light, AS responds rapidly within 1 h of light exposure and differentially with transcript specificity. Such an immediate light response on AS requires the direct participation of photoreceptors (Shikata et al. 2014, Wu et al. 2014). Energy and retrograde signals also regulate light-mediated AS (Petrillo et al. 2014, Hartmann et al. 2016, Mancini et al. 2016). The detailed mechanism of how these signaling pathways modulate splicing activities is still less explored. Recent findings of splicing factors RRC1 and SFPS in light regulation of AS shed light on the molecular mechanism of AS regulation mediated by photosensory phytochromes (Shikata et al. 2012, Xin et al. 2017). Other potential factors participating in the regulatory mechanism remain to be discovered. AS of individual regulatory genes has a potential impact on plant growth and development; however, the global pattern of AS in other genes such as metabolic genes may have an even stronger influence on plant growth. This possibility raises an unanswered question of how light can regulate AS with transcript specificity. Emerging evidence of cross-talk among the chromatin landscape, transcription and AS may provide an explanation because light can regulate both AS and chromatin status (Guo et al. 2008, Fisher and Franklin 2011, Luco et al. 2011, Li et al. 2012, Shikata et al. 2014, Wu et al. 2014, Herzel et al. 2017). The challenge will be to determine whether AS induced by light is due to changes in the chromatin landscape and the associated molecular mechanism. Another possibility is modulating the activities of splicing regulators/factors by light signaling, such as altering binding specificity and affinity for RNA targets via post-translational modification. These potential mechanisms require further investigation. The popular RNA-seq method in recent years is short-read sequencing. An advantage of this method is the production of a large quantity of reads that allows for detection of transcripts of low abundance with reasonable quantification of the expression level. However, the technique is limited in that it usually generates a false prediction of full-length transcripts, especially those with multiple AS events or from paralog genes. The optimal method is to sequence full-length transcripts directly with a suitable analysis method to determine the expression level. Although short-read sequencing is limited in predicting full-length transcripts, it is still acceptable to identify and quantify AS events occurring on single or multiple transcripts of a gene. Development of the analysis platform that is more accurate, faster and consumes fewer computation resources is necessary. In addition, the extent to which cis-elements or structures (from one to three dimensions) within pre-mRNA molecules affect AS decisions remains unclear. The selection of splice sites is determined by splicing regulators and also by regulatory cis-elements on pre-mRNA. However, the regulatory cis-elements involved in light regulation of AS are poorly understood. Recently, RNA immunoprecipitation sequencing, and cross-linking and immunoprecipitation sequencing have been successfully established for plant systems (Xing et al. 2015, Meyer et al. 2017). Together with other biochemical approaches, target transcripts and binding sites of RNA-binding proteins involved in light regulation of AS can be further determined. Understanding how light signaling is transduced to affect the efficiency of pre-mRNA splicing and the biological significance of light-regulated AS in plant systems may have implications for crop improvement and, ultimately, the production of crops that can adapt to extreme environments. Acknowledgment We thank Laura Smales for copyediting. Funding This work was supported by the Academia Sinica [Postdoctoral Fellows Program (to Y.-L.C.)] and the Ministry of Science and Technology, Taiwan [grant no. MOST 1062311-B-001033-MY3] (to S.-L.T.)]. Disclosures The authors have no conflicts of interest to declare. 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Nature 419 : 182 – 185 . Google Scholar CrossRef Search ADS PubMed Abbreviations Abbreviations AS alternative splicing AltA alternative 3' (acceptor) splice site AltD alternative 5' (donor) splice site COP1 CONSTITUTIVE PHOTOMORPHOGENIC 1 ES exon skipping hnRNP heterogeneous nuclear ribonucleoprotein HPR HYDROXYPYRUVATE REDUCTASE IR intron retention MRG MORF RELATED GENE NGS next-generation sequencing NMD nonsense-mediated mRNA decay phyB phytochrome B RNA-seq mRNA sequencing RRC1 REDUCED RED-LIGHT RESPONSE IN CRY1CRY2 BACKGROUND 1 RRM RNA recognition motif RS arginine/serine-rich domain SFPS SPLICING FACTOR FOR PHYTOCHROME SIGNALING snRNP small nuclear RNP SPA3 SPA1-RELATED 3 SR serine/arginine-rich U2AF U2 auxillary factor © The Author(s) 2018. Published by Oxford University Press on behalf of Japanese Society of Plant Physiologists. All rights reserved. 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Alternative Splicing and Cross-Talk with Light Signaling

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© The Author(s) 2018. Published by Oxford University Press on behalf of Japanese Society of Plant Physiologists. All rights reserved. For permissions, please email: journals.permissions@oup.com
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Abstract

Abstract Alternative splicing (AS) is the main source of proteome diversity that in large part contributes to the complexity of eukaryotes. Recent global analysis of AS with RNA sequencing has revealed that AS is prevalent in plants, particularly when responding to environmental changes. Light is one of the most important environmental factors for plant growth and development. To optimize light absorption, plants evolve complex photoreceptors and signaling systems to regulate gene expression and biological processes in the cell. Genome-wide analyses have shown that light induces intensive AS in plants. However, the biochemical mechanisms of light regulating AS remain poorly understood. In this review, we aim to discuss recent progress in investigating the functions of AS, discovery of cross-talk between AS and light signaling, and the potential mechanism of light-regulated AS. Understanding how light signaling regulates the efficiency of AS and the biological significance of light-regulated AS in plant systems will provide new insights into the adaptation of plants to their environment and, ultimately, crop improvement. Introduction Alternative splicing (AS) is a widespread mechanism in eukaryotes in which two or more mRNAs are generated from the same precursor mRNA (pre-mRNA) by the use of different splice sites. AS adds a new level of complexity to the transcriptome and is still an underexplored field in plant research. Multicellular eukaryotes have similar gene numbers but with higher complexity compared with single-cellular eukaryotes which can be explained at least in part by the diversity of RNA transcripts from AS. The development of next-generation sequencing (NGS) has provided the opportunity to reveal transcriptome patterns in nucleotide resolution. NGS has shown that almost half of the genes in plants are alternatively spliced (Filichkin et al. 2010, Guo et al. 2010, Zenoni et al. 2010, Zhang et al. 2010, Marquez et al. 2012, Wu et al. 2014). The findings strongly indicate that intensive AS events occur in plant systems to produce a tremendous amount of mRNA and protein isoforms. This function probably plays an important role under changing environments because regulation at the post-transcriptional level allows for immediate responses to dynamic conditions. The importance of AS may be underestimated. Whether AS affects plant growth and development in response to environments is not clearly addressed. How transcriptome and proteome alteration due to AS contributes to biological processes in plants is still little elucidated. As sessile organisms, plants need constantly to adapt to fluctuating environmental conditions. Plants cope with environmental changes by reorganizing their metabolism and gene expression, reaching a new balance among growth, development and survival. Light, one of the most important environmental factors, provides the energy source for plant growth and development. To optimize light absorption, plants evolve complex sensing and signaling systems to regulate gene expression and biological processes in the cell. Photoreceptors, including mainly phytochromes (red and far-red light), cryptochromes (blue light), phototropins (blue light) and UVR8 (UV-B light), sense a different quality (wavelength), quantity (intensity) and direction of light to regulate photomorphological responses throughout the life cycle of plants. Accumulating data suggest that light regulation can occur at different stages of gene expression to control the abundance of functional gene products (see review in Wu 2014). Chromatin modification has been found to be tightly regulated by light (Guo et al. 2008, Fisher and Franklin 2011, Li et al. 2012). Several light signaling components were proposed to function in chromatin regulation (Schroeder et al. 2002). Light-regulated gene expression largely relies on the actions of light signaling transcription factors (Casal and Yanovsky 2005, Jenkins 2009, Chen and Chory 2011, Leivar and Quail 2011). Light also regulates gene expression via translational control. A global survey of transcripts under translational regulation during photomorphogenesis in Arabidopsis has been reported (Liu et al. 2012). Furthermore, light post-translationally controls the abundance of key regulators by ubiquitin-dependent protein degradation (Wei and Deng 2003, Lau and Deng 2012). Although light regulation is found in almost every stage of gene expression, whether light regulates pre-mRNA splicing is still unclear. By taking advantage of NGS and bioinformatics, several groups have observed global changes in AS patterns in response to light in plants (Shikata et al. 2014, Wu et al. 2014, Hartmann et al. 2016, Mancini et al. 2016). The data indicate that light regulates AS to alter the transcriptome globally. Further studies also showed that photoreceptors, splicing regulators and spliceosomal components participate in the light-dependent regulatory process (Shikata et al. 2012, Xin et al. 2017). This review focuses on the function and molecular mechanism of AS in response to light. Constitutive Splicing Versus AS A single mature mRNA can be produced by constitutive splicing from one set of splice sites on the pre-mRNA. Selection of the splice site is determined by cis-acting elements on pre-mRNA that contain exon splicing enhancers/silencers and intron splicing enhancers/silencers, as well as trans-acting regulators that include serine/arginine-rich (SR) proteins and heterogeneous nuclear ribonucleoproteins (hnRNPs) (Fig. 1A). SR proteins and hnRNPs recruited by regulatory cis-elements on pre-mRNA activate or suppress the selection of splice sites and assembly of spliceosomes, large RNP complexes composed of cis-acting elements of pre-mRNA, small nuclear RNPs (snRNPs) and non-snRNP splicing factors (Sharp 1994, Reddy 2001, Zhou et al. 2002). The primary step of spliceosome assembly is the 5' splice site recognition by the U1 snRNP and 3' splice site recognition by the U2 auxillary factors (U2AFs) and U2 snRNP (Fig. 1A). With the stepwise assembly of U4, U5 and U6 snRNPs, and disassembly of U1 and U4 snRNPs, the active spliceosome is formed to catalyze intron cleavage and exon ligation (see reviews by Will and Luhrmann 2011, Hoskins and Moore 2012, Lee and Rio 2015). Fig. 1 View largeDownload slide Regulation and types of alternative splicing (AS). (A) Spliceosome assembly is determined by the cis-acting elements exonic/intronic splicing enhancer (ESE/ISE, colored in green) and exonic/intronic splicing silencer (ESS/ISS, colored in red), together with trans-acting regulators serine/arginine-rich proteins (SR proteins) and heterogeneous nuclear ribonucleoproteins (hnRNPs). Splicing regulators recruited by regulatory cis-elements on pre-mRNA define exon–intron junctions by interacting with U1 or U2 small nuclear RNPs (U1 or U2 snRNPs). (B) Different types of AS events, including exon skipping/inclusion (ES/EI), intron retention (IR) and alternative donor (AltD) and acceptor sites (AltA). Solid line, constitutive splicing (CS); dashed line, AS. Fig. 1 View largeDownload slide Regulation and types of alternative splicing (AS). (A) Spliceosome assembly is determined by the cis-acting elements exonic/intronic splicing enhancer (ESE/ISE, colored in green) and exonic/intronic splicing silencer (ESS/ISS, colored in red), together with trans-acting regulators serine/arginine-rich proteins (SR proteins) and heterogeneous nuclear ribonucleoproteins (hnRNPs). Splicing regulators recruited by regulatory cis-elements on pre-mRNA define exon–intron junctions by interacting with U1 or U2 small nuclear RNPs (U1 or U2 snRNPs). (B) Different types of AS events, including exon skipping/inclusion (ES/EI), intron retention (IR) and alternative donor (AltD) and acceptor sites (AltA). Solid line, constitutive splicing (CS); dashed line, AS. There are four basic types of AS events commonly observed. Elimination of splice site selection leads to intron retention (IR) or exon skipping (ES). Selection of distinct splice sites generates alternative 5' (donor) or 3' (acceptor) splice sites (AltD or AltA) (Fig. 1B) (see reviews in Reddy 2007, Syed et al. 2012). AS events could also simultaneously occur on a single pre-mRNA to produce more diverse transcripts from the same gene. Alternatively spliced transcripts were found early in expressed sequence tags (Iida et al. 2004, Campbell et al. 2006, Wang and Brendel 2006a, Barbazuk et al. 2008). With recent emerging NGS techniques, mRNA sequencing (RNA-seq) has quickly become widely used to identify AS events with high resolution. Over the past decade, the number of alternatively spliced genes identified has increased significantly. In Arabidopsis, >60% of intron-containing genes are reported to be alternatively spliced (Filichkin et al. 2010, Marquez et al. 2012). Analyses in other plant species provided similar results (Guo et al. 2010, Zenoni et al. 2010, Zhang et al. 2010, Wu et al. 2014). IR is the most predominant AS form in plants, whereas ES is prevalent in mammalian cells, which suggests differences in regulation of AS in animals and plants. Impact of AS in Plants AS events bring a different functional meaning to gene products. In terms of IR, most IR events generate unproductive transcripts that contain a premature termination codon in the retained intron or the downstream coding region and are potentially subjected to the nonsense-mediated mRNA decay (NMD) pathway (Kalyna et al. 2012). AS-coupled NMD is an important mechanism to regulate the level of functional transcripts (Reddy et al. 2013, Hamid and Makeyev 2014, Filichkin et al. 2015), which could be essential for plants to respond rapidly to fluctuating environmental conditions. AS events also cause loss or gain of function in protein products, such as producing proteins with or without additional functional domains. These domain-containing or domain-less proteins might have changed protein properties such as subcellular localization, stability, activity or protein interaction that may regulate the activities of full-length proteins. Some gene transcripts are alternatively spliced during environmental changes. For example, light promotes selection of an alternative 5' splice site within intron 12 of HYDROXYPYRUVATE REDUCTASE (HPR) transcripts in pumpkin (Mano et al. 2000). The HPR mRNA isoform induced under light conditions encodes a truncated protein localized in the cytosol because of loss of the peroxisomal targeting sequence at its C-terminus. Light also promotes AltD and IR of SPA1-RELATED 3 (SPA3) transcripts (Shikata et al. 2014). Alternatively spliced isoforms of SPA3 lacking part of the WD-40 repeat domains have a dominant-negative effect to the formation of the endogenous CONSTITUTIVE PHOTOMORPHOGENIC 1 (COP1)–SPA3 complex in ubiquitin-dependent protein degradation. Overexpressing the alternatively spliced isoforms of light signaling factors COP1 and PHYTOCHROME INTERACTING FACTOR 6 in Arabidopsis also has dominant-negative effects in photomorphological control (Zhou et al. 1998, Penfield et al. 2010). AS is particularly rich in gene transcripts involved in flowering time control (Terzi and Simpson 2008). For example, FCA encodes a plant-specific RNA-binding protein that functions in the autonomous pathway to prevent the accumulation of FLOWERING LOCUS C, the potent repressor of flowering (Macknight et al. 1997). Arabidopsis FCA produces several AS isoforms mainly caused by AS at intron 3 (Quesada et al. 2003). This AS pattern of FCA is conserved among plant species (Lee et al. 2005). Regulated expression of splicing variants of flowering-related genes may affect flowering time control. Mutations in pre-mRNA splicing-related genes also led to misregulation of flowering time (Terzi and Simpson 2008). Deficiency in the PRE-mRNA PROCESSING FACTOR 39, a component of U1 snRNP that functions in recruiting U1 snRNP to the 5' splice site to initiate spliceosome assembly, delays flowering in Arabidopsis (Lockhart and Rymond 1994, Wang et al. 2007). Mutation, knockdown or overexpression of other splicing factors such as SR30 (a SR protein), U2AF35 (for U2 snRNP assembly), EARLY FLOWERING 5 (interacts with U5 snRNP) and ENHANCED SILENCING PHENOTYPE 5 (a DEAH RNA helicase) all affect flowering time (Lopato et al. 1999, Noh et al. 2004, Herr et al. 2006, Wang and Brendel 2006b). These findings clearly reveal the tight relationship between regulation of pre-mRNA splicing and flowering time control. Because flowering induction in plants largely depends on environmental cues such as day length, light quality and quantity, and temperature, flowering time control mediated by environmental factors may be regulated by AS. AS patterns are diversified by combinations of regulatory cis-elements and splicing factors, and differential expression and post-translational modification of splicing factors in different cell types, tissues, developmental stages and environmental conditions, which tremendously increases transcriptome complexity and proteome diversity. With more global analyses identifying cell-, tissue- and condition-specific AS in plants, the functional roles of AS in plants for growth and developmental control as well as the response to environmental changes can be further clarified. Genome-Wide Analyses of AS in Response to Light In plants, many gene transcripts undergo AS in response to abiotic and biotic stresses (see reviews by Mastrangelo et al. 2012, Staiger and Brown 2013). Recently, an increasing number of transcriptome-wide studies based on RNA-seq provided evidence that AS globally responds to light in plants (Shikata et al. 2014, Wu et al. 2014, Hartmann et al. 2016, Mancini et al. 2016). RNA-seq in Arabidopsis showed that 1,505 genes (6.9% of Arabidopsis genes) undergo changes in the AS level of their transcripts within 1 h of exposure to red light (Shikata et al. 2014). Regulation of these gene transcripts also depends on phytochromes. In the moss Physcomitrella patens, 8.4% and 8.9% of AS events rapidly respond to red and blue light, respectively (Wu et al. 2014). Responsiveness of these light-dependent AS events is reduced in phytochrome-deficient and -knockout mutants, which suggests that phytochromes participate in regulating AS upon red light irradiation (Wu et al. 2014). The occurrence of light-regulated AS in Physcomitrella is comparable with that in flowering plants and reveals its importance during land colonization of aquatic photosynthetic organisms. Findings from both Arabidopsis and Physcomitrella suggest that photoreceptors, at least phytochromes, primarily participate in regulating AS and that this mechanism is conserved in land plants (Fig. 2A). Fig. 2 View largeDownload slide Potential mechanism of light-regulated AS. Four models are proposed in this review. (A) Phytochromes (Pfrs) activated by light interact with splicing factors (RRC1 and SFPS) to regulate AS. Other splicing factors (SFs) also potentially participate in the regulation. (B) Light-induced energy and retrograde signaling from plastids regulates AS via AS of RS31 or other SF genes. (C and D) Two models, the kinetic-coupling and chromatin-adaptor models, are proposed to explain the potential mechanisms. Based on the kinetic-coupling model, chromatin accessibility caused by the light-altered chromatin landscape affect the speed of transcription, which further regulates AS. Fast transcription elongation causes skipping of splice sites. Slow elongation of transcription allows recognition of weak splice sites. In contrast, the chromatin-adaptor model suggests that the light-altered chromatin mark serves as an anchor for histone adaptor binding, which further recruits splicing factors to regulate AS. Fig. 2 View largeDownload slide Potential mechanism of light-regulated AS. Four models are proposed in this review. (A) Phytochromes (Pfrs) activated by light interact with splicing factors (RRC1 and SFPS) to regulate AS. Other splicing factors (SFs) also potentially participate in the regulation. (B) Light-induced energy and retrograde signaling from plastids regulates AS via AS of RS31 or other SF genes. (C and D) Two models, the kinetic-coupling and chromatin-adaptor models, are proposed to explain the potential mechanisms. Based on the kinetic-coupling model, chromatin accessibility caused by the light-altered chromatin landscape affect the speed of transcription, which further regulates AS. Fast transcription elongation causes skipping of splice sites. Slow elongation of transcription allows recognition of weak splice sites. In contrast, the chromatin-adaptor model suggests that the light-altered chromatin mark serves as an anchor for histone adaptor binding, which further recruits splicing factors to regulate AS. Besides photoreceptor-mediated regulation of AS, other light-triggered signaling pathways may modulate the global pattern of AS (Fig. 2B) (Hartmann et al. 2016, Mancini et al. 2016). Hartmann et al. showed the differential expression of several hundred AS events in etiolated Arabidopsis seedlings undergoing photomorphogenesis upon blue, red or white light irradiation (Hartmann et al. 2016). By characterizing representative AS events, the authors suggested that photoreceptors are involved in only monochromatic but not white light-mediated regulation of AS. Furthermore, they demonstrated that exogenous sugar supply produced similar AS changes to light exposure, which suggests that energy availability plays a role in controlling AS in plants. Plastid to nucleus signaling has also been suggested to regulate AS (Petrillo et al. 2014, Mancini et al. 2016). RNA-seq analysis of Arabidopsis seedlings showed that treatment with an acute light pulse in the middle of the night affected the AS events of 382 genes (Mancini et al. 2016). Characterization of the splicing pattern of splicing factor gene transcripts indicated that AS was not impaired in a quintuple phytochrome mutant, which provides evidence of photoreceptor-independent control of AS in plants (Mancini et al. 2016). This result echoes an earlier study showing a retrograde signal also regulates AS of an SR protein gene transcript in the light response (Petrillo et al. 2014). Although the mechanism of energy and plastid to nucleus signaling is not clear, these results expand the view of light-mediated regulation for AS. In summary, photoreceptor, plastid and energy signaling for splicing regulation can be present simultaneously in plant cells, or occur in different cell types, tissues and developmental stages. These pathways can co-exist to provide multilayer regulation for gene expression. Potential Mechanism of Light-Regulated AS Many gene transcripts undergo AS from dark to light within 1 h, which suggests that light-regulated AS is a rapid response (Shikata et al. 2014, Wu et al. 2014). Two forward genetic studies revealed that phytochromes directly affect pre-mRNA splicing by modulating splicing regulators (Fig. 2A) (Shikata et al. 2012, Xin et al. 2017). Two mutants, reduced red-light response in cry1cry2 background 1 (rrc1) and splicing factor for phytochrome signaling (sfps), were isolated by checking for photomorphogenic defects of Arabidopsis seedlings under red light (Shikata et al. 2012, Xin et al. 2017). Both RRC1 and SFPS encode splicing regulators and form speckles in the nucleus. RRC1 is an ortholog of human SR-like protein SR140 and contains an N-terminal RNA recognition motif (RRM) and a C-terminal arginine/serine-rich (RS) domain. The rrc1 mutant lacking the RS domain shows aberrant AS of several SR protein gene transcripts (SR34, SR34b, RS31, RS31a and RS40) (Shikata et al. 2012). Since the phytochrome B (phyB)-deficient mutant also showed aberrant in red light-dependent AS of RS31 and SR34b transcripts, it is likely that RRC1 regulates AS in a phyB-dependent manner. SFPS encodes an ortholog of human SR-like SPF45 that contains a conserved SF45 motif, a glycine-rich motif and an RRM at its C-terminus. Defects in SFPS alter global AS patterns (Xin et al. 2017). Similar to RRC1, SFPS also regulates AS of several SR genes. SFPS was shown to associate with phytochromes under red light, therefore phytochromes might regulate AS directly. The modulation of AS might be via U2 snRNP because both human SR140 and SPF45 are U2 snRNP-associated proteins (Lallena et al. 2002, Will et al. 2002). Details of the regulatory mechanism for RRC1 and SFPS need further study. Emerging evidence revealed a cross-talk among multiple layers of gene expression. In yeast and mammalian cells, pre-mRNA splicing occurs co-transcriptionally (see reviews by Luco et al. 2011, Herzel et al. 2017). The co-transcriptional splicing is regulated by chromatin landscapes, such as DNA methylation and histone modifications. Two models, the kinetic-coupling and chromatin-adaptor models, are proposed to explain the relationship between chromatin landscapes and AS (Fig. 2C, D) (Luco et al. 2011). In the kinetic-coupling model, chromatin landscapes affect the transcription elongation rate, which further regulates AS. For example, the relationship between IR and chromatin accessibility was explored recently in plants (Ullah et al. 2018). IR is enriched in DNase I-hypersensitive sites, which indicates that IR occurs at DNA opening. Increasing chromatin accessibility allows for fast elongation and promotes splice site skipping (Ullah et al. 2018). In the chromatin-adaptor model, histone modifications serve as anchors for adaptors to recruit splicing regulators (Luco et al. 2010). An example is the recent report on the link between histone modification and temperature-induced AS found in Arabidopsis (Pajoro et al. 2017). Histone H3 Lys36 tri-methylation contributes to differential AS in response to temperature elevation and serves as an anchor for binding a chromatin adaptor, MORF RELATED GENE (MRG). MRG possibly recruits splicing regulators to regulate AS (Pajoro et al. 2017). Although evidence is still lacking to support a co-relationship between light-mediated AS and histone modification, several studies investigating histone modification under different light conditions have unveiled this possibility (Guo et al. 2008, Fisher and Franklin 2011, Li et al. 2012). Besides primary regulation, which directly modulates splicing activities, light-induced transcription and AS of splicing regulator genes affect the expression and functions of splicing regulators. For example, Shikata et al. (2014) showed that seven SR protein genes, i.e. RS31, RS40, RS41, RSZ33, RSZ34, SR34a and SR34b, in Arabidopsis undergo AS in response to light. The AS of these SR protein genes may affect the expression and property of SR proteins that further adjust the transcriptome in the cell. Light-regulated transcription and AS could occur in different cell types, tissues, developmental stages and environmental conditions to affect differentially the abundance of transcripts of splicing regulator genes. Diversified expression of splicing regulators may further alter AS in different cells or under different conditions. These changes have indirect control and thus increase the complexity of the resulting transcriptome. Challenges and Perspectives With the development of NGS, AS in plants has been extensively investigated in recent years. The number of genes with AS that have been identified is growing substantially and is expected to increase with deeper and broader sequencing in different cells, tissues, developmental stages and environmental conditions. RNA-seq of time courses of plant response to environmental changes can be further used to monitor the dynamic changes of AS. AS is now known to be regulated in response to different environmental signals. In terms of light, AS responds rapidly within 1 h of light exposure and differentially with transcript specificity. Such an immediate light response on AS requires the direct participation of photoreceptors (Shikata et al. 2014, Wu et al. 2014). Energy and retrograde signals also regulate light-mediated AS (Petrillo et al. 2014, Hartmann et al. 2016, Mancini et al. 2016). The detailed mechanism of how these signaling pathways modulate splicing activities is still less explored. Recent findings of splicing factors RRC1 and SFPS in light regulation of AS shed light on the molecular mechanism of AS regulation mediated by photosensory phytochromes (Shikata et al. 2012, Xin et al. 2017). Other potential factors participating in the regulatory mechanism remain to be discovered. AS of individual regulatory genes has a potential impact on plant growth and development; however, the global pattern of AS in other genes such as metabolic genes may have an even stronger influence on plant growth. This possibility raises an unanswered question of how light can regulate AS with transcript specificity. Emerging evidence of cross-talk among the chromatin landscape, transcription and AS may provide an explanation because light can regulate both AS and chromatin status (Guo et al. 2008, Fisher and Franklin 2011, Luco et al. 2011, Li et al. 2012, Shikata et al. 2014, Wu et al. 2014, Herzel et al. 2017). The challenge will be to determine whether AS induced by light is due to changes in the chromatin landscape and the associated molecular mechanism. Another possibility is modulating the activities of splicing regulators/factors by light signaling, such as altering binding specificity and affinity for RNA targets via post-translational modification. These potential mechanisms require further investigation. The popular RNA-seq method in recent years is short-read sequencing. An advantage of this method is the production of a large quantity of reads that allows for detection of transcripts of low abundance with reasonable quantification of the expression level. However, the technique is limited in that it usually generates a false prediction of full-length transcripts, especially those with multiple AS events or from paralog genes. The optimal method is to sequence full-length transcripts directly with a suitable analysis method to determine the expression level. Although short-read sequencing is limited in predicting full-length transcripts, it is still acceptable to identify and quantify AS events occurring on single or multiple transcripts of a gene. Development of the analysis platform that is more accurate, faster and consumes fewer computation resources is necessary. In addition, the extent to which cis-elements or structures (from one to three dimensions) within pre-mRNA molecules affect AS decisions remains unclear. The selection of splice sites is determined by splicing regulators and also by regulatory cis-elements on pre-mRNA. However, the regulatory cis-elements involved in light regulation of AS are poorly understood. Recently, RNA immunoprecipitation sequencing, and cross-linking and immunoprecipitation sequencing have been successfully established for plant systems (Xing et al. 2015, Meyer et al. 2017). Together with other biochemical approaches, target transcripts and binding sites of RNA-binding proteins involved in light regulation of AS can be further determined. Understanding how light signaling is transduced to affect the efficiency of pre-mRNA splicing and the biological significance of light-regulated AS in plant systems may have implications for crop improvement and, ultimately, the production of crops that can adapt to extreme environments. Acknowledgment We thank Laura Smales for copyediting. Funding This work was supported by the Academia Sinica [Postdoctoral Fellows Program (to Y.-L.C.)] and the Ministry of Science and Technology, Taiwan [grant no. MOST 1062311-B-001033-MY3] (to S.-L.T.)]. Disclosures The authors have no conflicts of interest to declare. 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Nature 419 : 182 – 185 . Google Scholar CrossRef Search ADS PubMed Abbreviations Abbreviations AS alternative splicing AltA alternative 3' (acceptor) splice site AltD alternative 5' (donor) splice site COP1 CONSTITUTIVE PHOTOMORPHOGENIC 1 ES exon skipping hnRNP heterogeneous nuclear ribonucleoprotein HPR HYDROXYPYRUVATE REDUCTASE IR intron retention MRG MORF RELATED GENE NGS next-generation sequencing NMD nonsense-mediated mRNA decay phyB phytochrome B RNA-seq mRNA sequencing RRC1 REDUCED RED-LIGHT RESPONSE IN CRY1CRY2 BACKGROUND 1 RRM RNA recognition motif RS arginine/serine-rich domain SFPS SPLICING FACTOR FOR PHYTOCHROME SIGNALING snRNP small nuclear RNP SPA3 SPA1-RELATED 3 SR serine/arginine-rich U2AF U2 auxillary factor © The Author(s) 2018. Published by Oxford University Press on behalf of Japanese Society of Plant Physiologists. All rights reserved. For permissions, please email: journals.permissions@oup.com This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices)

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Plant and Cell PhysiologyOxford University Press

Published: May 2, 2018

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