Plant Cell Rep DOI 10.1007/s00299-014-1565-z

REVIEW

Role of microRNAs in aluminum stress in plants Huyi He • Longfei He • Minghua Gu

Received: 30 December 2013 / Accepted: 2 January 2014 Ó Springer-Verlag Berlin Heidelberg 2014

Abstract Aluminum (Al) stress is a major factor limiting crop production. The primary symptom of Al toxicity is to inhibit root growth. Plant responses to Al require precise regulation of gene expression at transcriptional and posttranscriptional levels. MicroRNAs (miRNAs) are 20–23 nucleotides length non-coding RNAs, which promote the cleavage of target mRNAs. We have summarized some Al-responsive miRNAs identified, especially proposed the regulatory roles of miR319, miR390, miR393, miR319a.2, and miR398 in Al stress signaling network. The cross-talk between miRNAs and signaling pathways also has been discussed. Keywords MicroRNAs  Al stress  miRNAs biogenesis  Target mRNAs  Signal pathways

Introduction Aluminum (Al) toxicity is a major limiting factor of plant production on acidic soils. Excess Al3? interferes cellular redox equilibrium and boosts the accumulation of reactive oxygen species (ROS), resulting in oxidative damage. For better adaption to acid soils, plants have evolved

Communicated by N. Stewart. H. He  L. He  M. Gu College of Agronomy, Guangxi University, Nanning 530004, People’s Republic of China H. He (&) Cash Crops Research Institute, Guangxi Academy of Agricultural Sciences, Nanning 530007, People’s Republic of China e-mail: [email protected]

mechanisms to improve their survival. These mechanisms were divided into exclusion mechanisms from root and tolerance mechanisms in the symplast (Ryan et al. 2011). The best described mechanism is the intracellular Al chelation by organic acids, mainly including citric, oxalic, and malic acid (Ma et al. 1997). MicroRNAs (miRNAs) are a class of non-coding small RNAs composed of 20–23 nucleotides, which are mainly located in intergenic region or intron reverse repeated region. Its primary transcripts are capable of forming characteristic stem-loop structures (Bartel 2004). As the first found miRNA, lin4 is involved in developmental regulation of Caenorhabditis elegans (Lee et al. 1993). Plant growth, development, and stress responses are dependent on reasonable regulation of gene expression. As negative regulators of gene expression, miRNAs play important roles in post-transcriptional regulation of plant genome. The first plant miRNA reporter, Reinhart et al. (2002) identified 16 miRNAs from 200 cDNA clone of small RNA library in Arabidopsis. Theymodulated organism morphological architecture, hormonal secretion, signal transduction, and plant responses to environmental stress, by regulating gene expression via slicing and translational inhibition of target mRNAs. It is recently demonstrated that miRNAs are involved in the responses to heavy metal stresses in plants (Huang et al. 2009). By guiding post-transcriptional cleavage or translational suppression or DNA methylation, miRNAs negatively regulate the expression of target mRNAs (JonesRhoades et al. 2006). Because of high complementary pairing between miRNAs and their target genes, research progress of plant miRNAs is extremely rapid together with extensive application of model plant Arabidopsis thaliana. miRNAs may be one of molecular mediators associated with responses to Al stress. As a key element, the

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modulation of miRNA expression can be implicated in Al toxicity and Al tolerance (Lima et al. 2011). However, the involvement of miRNAs in Al stress is largely unknown. In this review, we focus on the recent research results about miRNAs and explore the regulatory role of miRNAs in Al stress responses.

Biogenesis, functions and targets of miRNAs Most of the primary miRNAs are transcribed by RNA polymerase II (Voinnet 2009). As a kind of RNase III, Dicer enzyme is specific for double-strand RNA with multi-structure domain. Further, this double-strand stemloop pri-miRNA can be processed in short miRNAs (smiRNAs) and/or long miRNAs (l-miRNAs). Dicer-like enzyme is responsible for the slicing of miRNA precursor (pre-miRNA). In A. thaliana, there are four Dicer-like genes, namely DCL1, DCL2, DCL3, DCL4, but only DCL1 is required for miRNA processing. Precise slicing of Dicerlike enzyme on pre-miRNA is central procedure of miRNA maturation. Owing to nuclear location sequence (NLS) of DCL1, DCL1-hyponastic leaves 1 (HYL1) compound first cleave primary miRNA into pre-miRNA, which is sliced into double-strand miRNA/miRNA*. To stabilize miRNA, 30 -terminal of miRNA/miRNA* is methylated by HUA ENHANCER1 (HEN1) protein with two dsRNA binding domains (RBD) and one NLS. Under the help of Exportin25 homology hasty (HST) transport protein, most of the methylated miRNA/miRNA* are transferred from nucleus to cytoplasm. Argonaute (AGO) protein families are principal members of RNA-induced silencing complex (RISC). There are ten AGO proteins in A. thaliana. While mature miRNA combines with RISC in cytoplasm, target mRNA recognition by miRNA would be degraded or inhibited at translational level. On the other hand, l-miRNAs can be processed through two pathways: one is that DCL3-sliced pri-miRNA is methylated by HEN1, another is that polymerase IV and RNA-dependent RNA polymerase (RDR) are involved in l-miRNAs biogenesis. The maturel-miRNA combines with AGO4 and guides domains rearranged methyltransferase 2 (DRM2)-catalyzed de novo DNA methylation. Compared with other oligonucleotides, the characteristics of miRNAs are as follows: the length of plant pre-miRNA ranges from twenties to hundreds; 50 terminal of mature miRNA is a phosphate base and 30 terminal is hydroxyl. Almost all miRNAs originate from the processing of same pre-miRNA arm and exist with the form of single copy, multi-copy or gene cluster. After being incorporated into RISC, mature miRNA regulates the expression of target genes through three mechanisms (Bartel 2004). If miRNA is completely complementary with target mRNA, it induces specific slicing of

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target gene’s mRNA. This is major pathway of miRNA action in plants. 30 -terminal of miRNA is located in PAZ structure domain but targeted mRNA in Piwi structure domain. When miRNA and target mRNA recognize each other, RNase hydrolyzes the corresponding residual phosphate by binding with 11th or 12th alkali base of target mRNA. Subsequently, 50 -terminal sequence of target molecule would be degraded. Another mechanism is to inhibit the translation of functional proteins by combining target gene’s mRNA. The last one is to silence multi-genes at transcriptional level via chromosomal isochromatin. Comparatively, miRNA sequences between different species are conserved, but their expressive patterns of time and space are highlyspecific. In general, plant miRNA from non-coding zone of gene is an independent transcript unit. Most of target genes are transcription factors related to developmental mode in plants. These processes include hormonal signal transduction, cell metabolism, organism differentiation, floral formation, and reproduction. miRNAs can regulate target genes at transcriptional and translation levels. Various stresses regulate the expression of miRNAs differently such as miR169 and miR395. In different species, the same stress induces contrastive responses of miRNAs. For instance, miR167 was up-regulated in Arabidopsis but suppressed in maize upon salt stress (Khraiwesh et al. 2012). To fine-tune DCL1 accumulation, miR162 was identified to cleave DCL1 (Xie et al. 2003). There is an analogous feedback mechanism between miR168 and its target AGO1 (Vaucheret et al. 2004). The targets of miR172 are apetala 2 (AP2)-like genes, which control the transition of different developmental phase (Lauter et al. 2005). Also squamosa promoter binding-like (SPL) family members targeted by miR156 control the transition from vegetative to reproductive phase (Wu and Poethig 2006). SPL7 can bind directly to GTAC motifs, which are present in the promoter of miR397 and miR408 (Yamasaki et al. 2009). Auxin response factor (ARF) family members targeted by miR167 regulate auxin signaling (Wu et al. 2006). TEOSINTE BRANCHED/CYCLODIDEA/PCF (TCP), miR319 target, binding to promoter elements is required for the expression of proliferating cell nuclear antigen (PCNA) gene (Kosugi and Ohashi 1997). miR390 and its target TAS3 are related to heavy metal toxicity in different plants. The target of miR164 is NAM/ATAF/CUC (NAC1) mRNA induced by auxin. Positive transcription factor coded by NAC1 can down-regulate the level of transport inhibitor response 1 (TIR1). The F-box auxin receptors TIR1/AFBs (F-box auxin receptors) and basic helix-loophelix (bHLH) transcription factors are the targets of miR393. TIR1 regulates auxin signaling positively. As the first identified miRNA regulated by oxidative stress, ‘miR398’s’ targets are the Cu/Zn superoxide dismutase

Plant Cell Rep Table 1 miRNAs related to aluminum stress responses miRNAs

Response

miR319

–

miR166

Targets

Targets functions

References

TCP

Floral development

Chen et al. (2012)

HD-Zip

Dorsoventral leaf polarity

Zhou et al. (2008)

miR529

Zhou et al. (2008)

miR160

ARFs

Auxin signaling

Zhou et al. (2012)

miR162

DCL1

miRNA pathway

Xie et al. (2003)

miR164

–

NAC, CUP

Lateral root and axillary meristem development

Zhou et al. (2012)

ARF6/8

Auxin signaling

Wu et al. (2006)

miR168

AGO1

miRNA pathway

miR169

NFY

miR167

Vaucheret et al. (2004) Khraiwesh et al. (2012)

miR171

SCL

Floral development

Zhou et al. (2008, 2012)

miR172 miR396

Developmental phase transition

–

AP2-like GRF

Lauter et al. (2005) Zhou et al. (2012)

miR393

?

TIR1/AFBs

Auxin signaling

Zhou et al. (2008), Sunkar and Zhu (2004)

bHLH miR395

?

miR397

APS

Sulfate starvation

Jones-Rhoades and Bartel (2004)

LAC

Metal complexation

Yamasaki et al. (2009) Zhou et al. (2008), Sunkar et al. (2006)

miR398

?

CSD, CCS, COX5b.1

Cu stress response

miR399

?

E2-UBC

Phosphate starvation

Chiou et al. (2006)

miR408

?

LAC

Photosynthesis

Yamasaki et al. (2009)

miR319a.2

?

Bozhkov et al. (2005)

miR156 miR159

–

Metacaspase

PCD

SPL3

Developmental phase transition

Wu and Poethig (2006)

MYB, TCP

Floral development

Huang et al. (2009), Fahlgren et al. (2007)

AFB auxin signaling F-box, AGO argonaute, AP2 apetala 2, APS ATP sulfurylases, ARF auxin response factor, CCS Cu chaperone for SOD, COX cytochrome oxidase, CSD Cu/Zn SOD, DCL dicer-like, GRF growth regulating factor, HD-zip homeodomain leucine zipper, LAC laccases, MYB myeloblastosis, NAC NAM/ATAF/CUC, SCL scarecroe-like, SPL squamosa promotor binding-like, TAS3 trans-acting siRNA 3,TCP teosinte branched cycloidea proliferating cell factor, TIR transport inhibitor response, ? up-regulated, - down-regulated

(CSD) and the 5b subunit of mitochondrial cytochrome oxidase (COX5b.1). Upon sulfate starvation, the increase of miR395 expression led to the reduction of ATP sulfurylases (APS) and sulfate transporter 2 (SULTR 2) (JonesRhoades and Bartel 2004). During phosphate starvation, up-regulated miR399 controls Pi homeostasis by targeting phosphate 2 (PHO2) (Chiou et al. 2006). Under Al stress, some genes such as ARF, domain-containing disease resistance protein (NB-ARC), LRR-TIR, cation-transporting ATPase, Myb, and NAM were found to be cleaved in wild soybean (Zeng et al. 2012). The targets of other miRNAs are listed (Table 1).

Role of miRNAs in Al stress The inhibition of root elongation is the primary symptom of Al toxicity (Kochian et al. 2005). As a result, plant roots become stunted and brittle, and the root apices become swollen and damage (Clarkson 1965). In such response to Al, miRNAs play important roles in root developmental regulation. miRNA164 modulates lateral root development

by regulating family members of transcription factors with NAC (NAMAATAFCUC) domain, such as cup-shapedcotyledon 1 (CUC1), CUC2, NAM, NAC1 (Laufs et al. 2004). Among them, NAC1 can promote lateral root growth in Arabidopsis through conversion of hormonal signal pathways, but miR164 can induce the degradation of endogenous and transgenic nac1 mRNA, weaken auxin signal to inhibit lateral root growth. Auxin can induce the expression of miR164 and promote the degradation of nac1 mRNA (Guo et al. 2005). miR160 controls the formation of root crown cells by negatively regulating the expression of ARFs ARF10 and ARF16. If the regulatory effect of miR160 on AFR16 is lost, multidirectional growth would occur in Arabidopsis (Mallory et al. 2005). Moreover, miR393 can modulate the expression of TIR1, which is involved in the formation of lateral root system by combining indole acetic acid (IAA) of E3 ubiquitin ligase-SCF compounds (Si-Ammour et al. 2011). In the model legume Medicago truncatula, the expression of partial miRNAs can be induced by Al. As the target of Osa-miR604, wall-associated kinase (WAK)-like protein was involved in Al responses (Hou et al. 2005). Expression

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Plant Cell Rep Fig. 1 Schematic illustration of miRNAs in responses to Al stress

Al stress

Stimulus

H2O2

Signal

miRNAs

miR319

miR390 TAS3

TFs

miR393

TIR1/AFBs and bHLH

miR398

miR319a.2

CSD1/2 and CCS

tasiARFs TCP Target genes

Response

of miR393, miR171, miR319, and miR529 was up-regulated, while miR166 and miR398 were down-regulated exposure to 50 lM Al (Zhou et al. 2008). The regulatory mechanisms of miR398 include the cleavage and translation inhibition of target mRNAs, which encode copper chaperone for SOD (CCS1) and CSD2 (Beauclair et al. 2010). Chen et al. (2012) revealed that miR159, miR160, miR319, miR396, and miR390 were down-regulated in response to Al. After 8 h of 450 lM Al treatment, 13 miRNAs (miRNA156, miRNA169, miRNA172, miRNA393, miRNA395, miRNA398, miRNA408,miRNA415, miRNA426, miRNA808, miRNA809, miRNA813) were down-regulated and six (miRNA160, miRNA166, miRNA168, miRNA399, miRNA528, miRNA819) were up-regulated in roots of Oryza sativa ssp. japonica cv. Nipponbare. In roots of Oryza sativa ssp. indica cv. Embrapa Taim, five miRNAs (miRNA395a, miRNA408, miRNA393b, miRNA398a, and miRNA398b) were down-regulated and three (miRNA168a, miRNA528, miRNA399d) were up-regulated (Lima et al. 2011). In wild soybean BW69, three miRNAs (miR164, miR156, miR1507) were down-regulated and seven (miR2218, miR862, miR1514, miR4415, miR396, miR403, miR1509) were up-regulated under 50 lM Al stress (Zeng et al. 2012). 1 % Al2O3 nanoparticles extremely increase the expression of miR395,miR397, miR398, and miR399 in tobacco plants (Burklew et al. 2012). The results suggested that miRNAs play important roles in the regulation of plant Al stress responses. As shown in Fig. 1, miR319 in roots is repressed in response to Al, resulting in the degradation of TCP to affect root growth (Chen et al. 2012). The regulation of miR319 would depend on the different plant species, the different exposure time, and Al concentration. Marin et al. (2010) demonstrated that ARFs play critical roles in lateral root development. Under Al stress, miR390 of plant roots is suppressed, which lead to the accumulation of TAS3 transcript, subsequently the decrease of trans-acting small

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Auxin signaling

Metacaspase

ROS

ARFs

Root elongation inhibition

PCD

interference RNAs (tasiARFs), the degradation of ARFs, and the inhibition of lateral root growth (Zhou et al. 2012). Al induces miR393, which would lead to the repression of TIR1/AFBs and bHLH, thus the inhibition of root growth. Oxidative stress underlies Al-mediated cellular toxicity (Boscolo et al. 2003). Al-induced expression of miR398 can inhibit the activities of CSD1/2 and CCS, thus result in more ROS production, which is common response to Al toxicity (Zhou et al. 2008). As a secondary effect, miR398 of 21 days old tobacco seedlings was induced after exposure to Al oxide nanoparticles (Burklew et al. 2012). H2O2 down-regulates the expression of miR319a.2 (Li et al. 2011), which target metacaspase was involved in programmed cell death (PCD) in plants (Bozhkov et al. 2005). The reduced expression of miR319a.2 under Al stress might result in an increase in PCD, consistent with previous results that Al-induced PCD possibly via a ROS-activated signal transduction pathway (Pan et al. 2001). So plant miRNAs regulate the expression of their target gene through defense against oxidative stress and signal transduction pathways (Gielen et al. 2012).

Cross-talk between miRNAs and signal pathways in plants miRNAs can affect signal transduction pathways, especially hormonal regulation pathways in plants. Mutation of miR164 results in the interruption of auxin signal pathway, but overexpression of miR164 down-regulates the expression of NAC1 gene and reduces the formation of lateral root. Because there exists gibberellin (GA) response elements (GARE) in the upstream of MIR-166a and MIR319a gene, GA treatment decreases the expression of miR166 and miR319. miR393 modulates auxin signaling via the regulation of TIR1. Arabidopsis F-box protein TIR1 is not only an auxin receptor, but also a very important

Plant Cell Rep

component of E3 ligase complex. In response to hormone, SCFTIR1 complex combine directly with auxin to degrade AUX/IAA protein (Liu et al. 2009). Conclusion and perspective The networks of Al uptake, transport, chelation, sequestration, and detoxification have been extensively studied. As crucial components of gene regulatory network, miRNAs can regulate several protein-coding genes, which are implicated in the same pathway. To date, our understanding of Al-responsive miRNAs is limited. For instance, whether these Al-responsive miRNAs are tissue-specific? Whether the alterations in miRNA expression are secondary consequence of Al stress? How to predict novel Al-responsive miRNAs with bioinformatic method? The identification of Al-responsive miRNAs and expression analysis of their target genes will provide new insights into Al toxicity in plants. To elucidate novel roles of miRNAs in the response to Al stress, we can employ high-throughput sequencing combined with computational analysis to survey more novel Al-responsive miRNAs. Exploring mRNA sequence complementary with these miRNAs can identify their target genes. The interplays between miRNAs and genetic or epigenetic factors should be investigated in the future research (Hou et al. 2011). The kinetics of miRNAs and target regulation over a time-course of Al exposure may vary in plant species with differential growth habits and genotypic backgrounds, so phenotypic analysis of plants with modulated expression of a specific miRNA or its targets will be helpful to better understand the role of miRNAs in signaling pathway of plant responses to Al stress. Manipulation of miRNA-guided gene regulation will contribute new strategies to engineering plants with improved Al tolerance. Acknowledgments This work was supported by the National Natural Science Foundation of China (No. 30960181 and 31260296) and 2011 Guangxi Innovation Program for Graduates (GXU11T31076).

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