Abstract
MicroRNAs (miRNAs), a type of endogenous non-coding small RNA, with a length of 20 to 24 nt, represses their target gene expression post-transcriptionally. There are a growing number of studies have discovered that miRNAs are found in animals and plants. Plant miRNAs are involved in growth and development, and they play an important role in physiological and biochemical regulation. This review mainly focuses on components of different miRNA processing pathways and how miRNA effectors inhibit the expression of target genes in plants. We discuss not only the various pathways affecting miRNA biogenesis, but also the different forms of miRNA effector pathways. Previous studies found that there have been some primary advances in the formation of miRNAs, we hope to provide a comprehensive introduction to the biogenesis of plant miRNAs.
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Introduction
MicroRNA (miRNA) is a class of eukaryotic endogenous non-coding small RNAs with a length of about 20 to 24 nt, which do not encode proteins and have no open reading frame. In 1993, the first members of miRNA, lin-4 and let-7, were found in Caenorhabditis elegans, and they were demonstrated to influence the expression of the target nuclear lin-14 through post-transcription and translation inhibition, thereby affecting the transition from larval L1 development to L2 (Lee et al. 1993; Wightman et al. 1993; Reinhart et al. 2000). Since then, a large number of miRNAs have been found in many plant species, including Solanum lycopersicum, Zea mays, Elettaria cardamomum Maton, Nicotiana tabacum, Arabidopsis thaliana and Oryza sativa et al. These miRNAs have been shown to play a vital role in the plant development and growth, as well as biological and abiotic stress physiology (Voinnet 2009; Silva et al. 2014; Wang et al. 2015a,2016; Ma et al. 2015; Yu et al. 2015,2017a; Feng et al. 2016; Leng et al. 2017; Lotfi et al. 2017; Zhang et al. 2019; Wu et al. 2019; Feng et al. 2020; Yang et al. 2020; Lakhwani et al. 2020). Like most mRNAs, MIR genes (genes encoding miRNA) are also transcribed by DNA-dependent RNA polymerase II (Pol II) and then undergo a series of transcriptional modifications including splicing of the 5′ cap and 3′ polyadenylation to form primary transcript pri-miRNAs (Kurihara et al. 2004; Kim et al. 2011). These pri-miRNAs containing partially complementary paired hairpin structures are able to be identified and cleaved by multiple protein complexes such as DCL1 (dicer-like1), double-stranded RNA-binding protein HYPONASTIC LEAVES (HYL1), C2H2-zinc finger structural protein SERRATE (SE), and G-patch structural protein TGH to form the precursor miRNA (pre-miRNA) (Kurihara et al. 2004; Kurihara et al. 2006; Dong et al. 2008; Ren et al. 2012a).
The 3′end of the processed double-stranded miRNAs (miRNA/miRNA*) can be methylated by HUA Enhancer 1 (HEN1) to prevent double-stranded miRNAs from by uridylation (Li et al. 2005; Yu et al. 2005). These double-stranded RNAs may be transferred from the nucleus to the cytoplasm under the action of HST (HASTY, the plant homolog of exportin-5/Exp5) and other unknown factors (Park et al. 2005). The miRNA* in the double-stranded miRNA is then degraded, leaving only the mature miRNA. The resulting mature miRNA can reduce gene expression via incorporation into ARGONAUTE (AGO1), which combines with other proteins to form the RNA induced silencing complex (RISC). The RISC complex then cleaves mRNAs or represses their translation (Baumberger and Baulcombe 2005). Overall, the maturation process of miRNAs can be summarized into three important aspects: transcription, post-transcriptional processing and the stabilization of miRNA after processing (Fig. 1).
A diagram of the miRNA biogenesis and effector pathway in plants. miRNAs are transcribed into primary miRNAs (pri-miRNAs) by DNA dependent RNA Polymerase II (Pol II) and then processed into precursor miRNAs (pre-miRNAs) by the action of D-body. The processed double-stranded miRNAs are then methylated by HEN1, and transported from the nucleus to the cytoplasm by HST. The resulting mature miRNA can reduce gene expression via incorporation into AGO1, which combines with other proteins to form the RISC. RISC has two forms of action, one is transcriptional cleavage, the other is translation repression
miRNAs play an irreplaceable biological role in plants and can affect various development stages, enabling complex regulation of plant growth as well as responses to biotic or abiotic stresses (Ori et al. 2007; Wu et al. 2009; Guo et al, 2005; Sunkar et al. 2006; Wang et al. 2012; Huang et al. 2018; Anjali et al. 2019). Therefore, a full understanding of miRNA transcription and processing is particularly important. This review mainly focuses on the many proteins involved in the biogenesis of miRNAs and how these miRNA function in downstream target genes (Table S1).
MIR gene transcription
The initiation of miRNA formation follows the same process as most genes, which involves DNA-dependent RNA polymerase II (Pol II). The initiation process of miRNA transcription, like many other genes, is often regulated by biotic and abiotic factors (Lee et al. 2004; Xie et al. 2005). The pri-miRNA is transcribed by Pol II during a process that is regulated by many transcription factors. For example, MED20A (Mediator20A), MED17 (Mediator17) and MED18 (Mediator18) are able to affect gene transcription by interacting with Pol II. Studies have found that the transcription complexes formed by MED20A, MED17 and MED18 are required for microRNA (miRNA) biogenesis due to the ability of these proteins to recruit Pol II to the promoters of miRNA genes. Interestingly, studies have found that the levels of miRNA and pri-miRNA are significantly decreased in the Arabidopsis mutants of med20a, med17 and med18 (Chadick et al. 2005; Kim et al. 2011).
In Arabidopsis it was shown that the NOT2_3_5 domain protein NOT2 interacts with Pol II and influences the transcription of miRNAs, while NO2a-1 and NO2b-1 mutants have significantly reduced pri-miRNA levels, indicating that NOT2a/b plays a key regulatory role in the transcription of miRNAs (Anand et al. 2007; Wang et al. 2013). In addition, CDC5, a protein containing the MYB domain, can bind to the promoter of MIR genes to affect the transcriptional activity of miRNAs (Zhang et al. 2013a).
Recent research has found that the disease resistance gene SNC1 can interact with the transcriptional co-suppressor TPR1 to reduce miRNA levels, suggesting that the R gene-miRNA-phasiRNA regulatory module plays an important role in plant immune responses (Cai et al. 2018).
Elongation is critical in the process of transcription, and conserved elongation factors play an important role in the transcription in animals and plants. The extension genes ELP2 and ELP5 have been shown to participate in the plant miRNA transcription process, while disruption of elongator reduces RNAPII occupancy at miRNA loci and suppresses pri-miRNA transcription. MIR genes eventually form pri-miRNA through RNA polymerase Pol II and other proteins, and cycling DOF transcription factors (CDF2) can accelerate the transcription of MIRs (Sun et al. 2015). A recent study found that SMA1 can affect the binding of Pol II to the promoter of MIR genes, while SMA1 can bind the promoter region of the gene that encodes the pri-miRNAs, which is necessary for MIR transcription (Li et al. 2018). Transcription of MIR genes play a very important role in the final formation of miRNA and further processing and modification can be carried out only after the transcription is complete.
miRNA post-transcriptional regulation
Processing of primary miRNAs and precursor miRNAs
Pri-miRNAs are processed into mature miRNAs by a series of intricate modifications. The length of the stem loop structure of the pri-miRNA varies, which results in different cleavage forms. Base to loop direction also matters and affects bidirectional processing (Zhu et al. 2013; Cuperus et al. 2010; Bologna et al. 2009; Song et al. 2010). DCL1 (Dicer-like1) was the first protein shown to be directly involved in the processing of pri-miRNA and pre-miRNA (Kurihara et al. 2004). There are four DCL genes (DCL1-4) in Arabidopsis, among which DCL1 plays the most crucial function in the processing of miRNAs, which are significantly decreased in the dcl1 mutant (Kurihara et al. 2004; Deleris et al. 2006). DCL1 is a homolog of the Drosophila gene Dicer and is similar to the Human Dicer gene (Bernstein et al. 2001; Macrae et al. 2006). DCL1 contains several conserved domains, including an N-terminal helicase domain (DExH-box RNA-helicase-C motifs), unknown domain DUF283, PAZ domain (PIWI/AGRONAUTE/ZWILLE), RNA ribonuclease domains (RNase III, RNase IIIa, RNase IIIb) and 1 or 2 double-stranded RNA-binding domains at the C-terminus. The PAZ domain can bind to the RNA ends, especially double-stranded RNA with a two-nucleotide protrusion at the 3′ end (Tagami et al. 2009; Schauer et al. 2002). Earlier research using miRNA163 as an example demonstrated that DCL1 can participate in the cleavage of pri-miRNA163, with DCL1 acting as the exonuclease (Kurihara et al.2004). The helicase domain provides energy for the cleavage function of DCL1 and is required for the processing of some specific miRNAs (Liu et al. 2012). DDL, is an RNA binding protein that participates in miRNA processing by interacting with pri-miRNA to promote the effective identification of pri-miRNA by DCL1 (Yu et al. 2008). Overall, DCL1 plays a critical role throughout the process of miRNA biogenesis.
After the transcription of a MIR gene, the pri-miRNA transcript is subjected to subsequent cleavage by the DCL1 processing complex and eventually forms a mature miRNA. In addition to the DCL1, there are many other protein factors in the DCL1 processing complex, some of which can interact with DCL1 to affect the accuracy and efficiency of processing.
HYL1 (HYPONASTIC LEAVES1) has been shown to interact with DCL1 to improve the accuracy of pri-miRNA cleavage (Kurihara et al. 2006). Mutants of HYL1 accumulate higher levels of pri-miRNAs and less mature miRNAs, indicating that HYL1 influences the content of mature miRNA by participating in the post-transcriptional processing of pri-miRNA (Dong et al. 2008). The N-terminus of HYL1 contains two double-stranded RNA-binding domains (dsRBD1 and dsRBD2), and the C-terminus contains protein interaction binding domains (Lu and Fedoroff 2000; Wu et al. 2007; Yang et al. 2010). Previous research has shown that the DsRBD2 domains in HYL1 can form homodimers, which affect the selection of cleavage sites in pri-miRNA and facilitates processing. However, disruption of this homodimer does not interfere with its interactions with other proteins, such as DCL1 and SE (Yang et al. 2010, 2014).
SERRATE is a C2H2 zinc finger protein which can also influence the recognition and cleavage efficiency of pri-miRNA by interacting with DCL1 (Dong et al. 2008). A decrease in miRNA content and an increase in pri-miRNA content were detected in the se-1 mutant, which has several pleiotropic phenotypes. The se mutant exhibits some similar developmental abnormalities as the hyl1 mutant. SE is localized in the nucleus where it interacts with HYL1 (Yang et al. 2006; Lobbes et al. 2006) and the core region of the SE protein may provide a platform for the interaction between HYL1 and DCL1. However, the interacting region of SE is not in the zinc finger region but in the middle and N-terminal region. Overall, it is thought to act as a scaffold protein, which affects the accuracy of miRNA processing through binding pri-miRNA to HYL1 and DCL1 proteins (Machida et al. 2011).
NOT2 protein can also act as a scaffold during miRNA processing, and mutants deficient in this protein have fewer pri-miRNAs and mature miRNAs. These findings indicate that NOT2 not only influences the formation of miRNAs at transcriptional level but also may influence the processing of miRNAs at post-transcriptional processing level (Anand et al. 2007; Wang et al. 2013).
The cap-binding protein complex (CBC) binds to the caps of all Pol II transcripts (Wen et al. 1998). In addition, CBP80 and CBP20 play a crucial role in the processing of miRNAs. Mutants of cbp80 and cbp20 lead to higher levels of pri-miRNA and less mature miRNAs. Similar to SE, CBP80/20 also acts to combine RNA with DCL1 and promote miRNA processing (Kim et al. 2008; Kierzkowski et al. 2009).
TGH is an RNA-binding protein containing domains with high similarity to G-patch and SWAP domains (Compressor-of-White-Apricot) (Calderon-Villalobos et al. 2005). The TGH protein has been found to be a critical part of the DCL1-HYL1-SE processing complex, with data showing that TGH regulates the levels of miRNAs by affecting the efficiency of cleavage of pri-miRNA (Ren et al. 2012a). However, TGH only regulates the abundance of miRNAs by promoting DCL1 cleavage efficiency but does not affect the accuracy of processing (Ren et al. 2012a).
Studies have shown that CDC5 and PRL1 in the MAC complex (MOS4-associated complex) participate in the processing of miRNAs. CDC5 not only affects miRNA genes at the transcriptional level, but also impacts processing steps. However, experiments such as Co-Immunoprecipitation and Bimolecular Fluorescence Complementation have shown that CDC5 can interact with DCL1 and SE, thereby influencing the cleavage efficiency of pri-miRNA and formation of mature miRNAs (Zhang et al. 2013a). PRL1 (an evolutionarily conserved WD-40 protein) can interact with CDC5 as well as with DCL1 and SE to promote the transcription of miRNA and the stability of pri-miRNA, but mutants of PRL1 do not show reduced interaction between CDC5 and DCL1.These results demonstrate that PRL1 may assist CDC5 in its function in the MAC complex and act as a component of the DCL1 complex to enhance primary miRNA processing (Zhang et al. 2014). In addition to the transcriptional level, CDF2 can affect the miRNA at the post-transcriptional level by interacting with DCL1 (Sun et al. 2015).
There are also many proteins that can influence the action of the DCL1 processing complex on pri-miRNA via indirect pathways. Phosphorylation plays a key role in the processing of miRNA, and the accuracy and stability of phosphorylation of HYL1 impact the processing of miRNA. C-terminal domain phosphatase-like 1 (CPL1/FRY2) interacts with HYL1 and SE proteins in the DCL1 processing complex, and CPL1 maintains the phosphorylation of HYL1 to ensure the accuracy of pri-miRNA cleavage, in which SE protein acts as a scaffold to regulate the interaction of HYL1 and CPL1 (Koiwa et al. 2002; Xiong et al. 2002; Manavella et al. 2012). In contrast, mitogen activated protein (MPK3) promotes the phosphorylation of HYL1 to reduce its activity. A significant decrease in miRNA levels was detected in the mutants of atmpk3 and atmpk6 (Raghuram et al. 2015). Arabidopsis thaliana K homology (KH) domain protein REGULATOR OF CBF GENE EXPRESSION 3 (RCF3) acts as a cofactor for miRNA processing via nuclear interactions with the phosphatases CPL1 and CPL2. RCF3 can interact with CPL1 and CPL2 to promote HYL1 dephosphorylation (Karlsson et al. 2015).
The protein phosphatase PP4 (Protein Phosphatase 4) and SMEK1 (Suppressor of MEK1) complex enables HYL1 dephosphorylation in order to enhance processing of miRNA by antagonizing the MAPK cascade and mediating HYL1 stability. SMEK1 can reduce the phosphorylation of HYL1 by inhibiting the activity of mitogen activated protein kinase MAPK, and also it can recruit PP4 protein to maintain the dephosphorylation of HYL1, thereby ensuring miRNA biogenesis (Su et al. 2017).
Recently, the regulatory subunit 3 (PP4R3A) in the phosphatase PP4 complex, together with two of the redundant catalytic subunit genes, PPX1 and PPX2, was shown to promote miRNA formation (Wang et al. 2019a). PP4R3A loss-of-function mutations have been shown to cause lower levels of miRNA, pri-miRNA and HYL1. However, the results of co-IP experiments showed that PP4R3A could not interact directly with HYL1 and SE proteins, suggesting that PP4 facilitates miRNA biogenesis at transcriptional and post-transcriptional levels by recruiting the microprocessor component HYL1 to MIR genes and nuclear dicing bodies (Wang et al. 2019a). Additionally, SHORT VALVE 1 (STV1), a conserved ribosomal protein, modulates miRNA process by promoting to recruit pri-miRNAs to the DCL1 (Li et al. 2017).
Mature pri-miRNA usually includes a 5′ end cap structure, a 3′ end poly-A tail structure and at least one stable neck loop structure. The cell cyclin-dependent protein kinase CDKF-1 plays a crucial role in the stabilization of pri-miRNA and the cdkf-1 mutant has lower levels of precursors and mature miRNAs (Hajheidari et al. 2012). In Arabidopsis, STABILIZED1 (STA1), a pre-mRNA processing factor 6 homolog, is also involved in the processing of miRNAs. Similar to other miRNA process-defective mutants, sta1 mutants accumulate levels of pri-miRNAs and decrease levels of mature miRNAs. STA1 indirectly participates in the processing of miRNAs by directly promoting pri-miRNA splicing and modulating DCL1 at the transcriptional level (Lee et al. 2006; Chaabane et al. 2013). CMA33 encodes a nuclear localized protein, XAP5 CIRCASIAN TIMEKEEPER (XCT), which can act as a transcriptional factor to regulate miRNA biogenesis by modulating the transcription of DCLs (Fang et al. 2015b).
SIC is a proline-rich protein, which can influence the function of the DCL1 processing complex by interacting with HYL1. The levels of miRNAs in the SIC loss-of-function mutants are significantly reduced (Zhan et al. 2012). Recent research has found that an importin-β-protein (KETCH1) indirectly facilitates processing of pri-miRNA through transport of HYL1 into the nucleus and thus contributes to the formation of the DCL1 processing complex (Zhang et al. 2017a). The main function of the MOS2 protein, which includes G-patch and KOW domains, is RNA binding (Zhang et al. 2005). The mos2 mutants have lower levels of mature miRNA, though MOS2 can neither interact with proteins in processing complex such as DCL1, HYL1 and SE nor localize to the D-bodies. It is thought that MOS2 may affect miRNA by recruiting pri-miRNA into D-bodies (Wu et al. 2013).
SMALL1 (SMA1), a homolog of the DEAD-box pre-mRNA splicing factor Prp28, participates in miRNA biogenesis by affecting the intron excision process of the MIR gene (Strauss and Guthrie 1994; Li et al. 2018). The transcriptional elongation proteins EPL2 and ELP5, in addition to influencing miRNA content at the transcriptional levels, can also participate in the processing of miRNA by interacting with DCL1 to localize DCL1 to the Dicer-like 1 complex (Fang et al. 2015a). Constitutive photomorphogenic 1 (COP1), a RING-finger E3 ligase, plays a crucial role in photomorphogenesis by destabilizing many light-regulated transcriptional factors and photoreceptors. COP1 can avoid the degradation of HYL1 in the cytoplasm by protease X under high light, thus regulating the processing of miRNA (Seo et al. 2003; Cho et al. 2014). SnRK2 kinase, a response factor for abscisic acid (ABA) and osmotic stress signals, has recently been found to reduce the accumulation of miRNA. SnRK2 phosphorylates HYL1 and SE in the DCL1 processing complex. These results demonstrate a significant role for SnRK2 kinases in the processing of miRNA and reveal a mechanism by which ABA and osmotic stress signaling are linked to miRNA biogenesis (Fujii and Zhu 2009; Yan et al. 2017). The RNA-binding protein FCA can also increase the levels of some miRNAs by affecting the process of pri-miRNA in response to temperature change (Jung et al. 2012).
CHR2/BRM is an ATPase in the SWI/SNF chromosome-remodeling complex, and chr2 mutants have a pleiotropic phenotype including altered miRNA expression. Recently, CHR2 was found to not only facilitate the production of pri-miRNA at the transcriptional level, but also reduce the accumulation of miRNA at the post-transcriptional level through interactions with the SE protein. The secondary structure of pri-miRNA is altered in the mutants of chr2, suggesting that CHR2 may influence the processing of miRNA by remodeling their secondary structures. CHR2 plays a crucial role in the positive and negative regulation of miRNA and is important for maintaining their balance in plants (Farrona et al. 2004; Hurtado et al. 2006; Clapier et al. 2017; Wang et al. 2018).
Further processing of miRNA and transport of pri-miRNA
The pri-miRNA is further modified by the DCL1 processing complex to form pre-miRNA, which is then cleaved to form double-stranded miRNA/miRNA* (Song et al. 2007; Kurihara et al. 2006). In this process, the pre-miRNA processing modification is critical. THO2, which encodes a core subunit of the plant THO/TREX complex, participates in miRNA biogenesis by recruiting miRNA precursors into the miRNA processing complex. The tho2 mutants have reduced levels of miRNA and increased precursor levels due to a failure to recruit precursors into the DCL1 processing complex (Reed and Cheng 2005; Furumizu et al. 2010; Francisco-Mangilet et al. 2015). Recent research has shown that the nucleotide transferase HESO1 (HEN1 SUPPESSOR1) is able to promote the uridylation of pre-miRNA. In Arabidopsis, HESO1, NTP6 and NTP7 contribute to pre-miRNA cytidylation. The addition of these tails to pre-miRNA can restore the cleaved pre-miRNA to full length, thus facilitating subsequent processing. In addition, uridylation regulated by HESO1 can also degrade pre-miRNAs that cannot be accurately processed (Song et al. 2019).
The final processed double-stranded miRNAs (miRNA/miRNA*) require further stabilization and modification in order to form mature miRNAs. The HEN1 protein plays a critical role in stabilizing and modifying double-stranded RNA. HEN1 is a methyltransferase with a binding site for double-strand miRNA at its N-terminal and a conserved C-terminal methylation domain. Therefore, HEN1 accelerates the processing of miRNA by improving the stability of double-stranded miRNAs through methylation (Yu et al. 2005).
In animals, the nuclear export receptor protein Exp5 (the nuclear export receptor Exportin5) can transport pre-miRNAs from the nucleus to the cytoplasm (Zeng and Cullen 2004; Lund et al. 2004). In Arabidopsis, the Exp5 homolog HASTY (HST) has been shown to modulate the processing of miRNA. There is a decreased level of miRNA in the Exp5 loss-of-function mutants, though there is insufficient evidence that HST is involved in the transport of miRNA. Because the accumulation of miRNAs in the nucleus and cytoplasm are not detected in mutants of hst, HST is thought to act more to stabilize miRNA than to transport it (Park et al. 2005). The THO/TREX complex is involved not only in the transport of mRNAs but also in the transport of miRNAs (Köhler and Hurt 2007). Overall, the exact mechanism of miRNA transport in plants is not fully understood and requires more investigation.
miRNA effector formation and function
RISC complex formation and miRNA loading
miRNAs regulate target gene expression by translational repression and post-transcriptional cleavage via the RISC complex. It was first reported in humans that miRNAs are loaded into the RNA-induced silencing complex (RISC) to modulate post-transcriptional silencing and translational repression (Gregory et al. 2005). Similar to animals, miRNAs in plants also form a RISC complex by interaction with AGO1 proteins. First, pre-miRNA binds to AGO proteins to form pre-RISC, after which the miRNA* in double-stranded RNAs is removed from the complex to form a mature RISC protein complex. The AGO1 protein is the crucial component of the RISC protein complex and is able to modulate its slicing activity (Baumberger and Baulcombe 2005; Eamens et al. 2009). In Arabidopsis, there are ten AGO proteins, among which AGO1, AGO2, AGO4, AGO7 and AGO10 have all been shown to have cleavage activity that indirectly affects the activity of different small RNAs (Mi et al. 2008; Takeda et al. 2008; Montgomery et al.2008; Zhu et al. 2011). In addition to the PAZ domain that binds to the miRNA, the AGO proteins include the PIWI domain, a Mid domain and a cap-binding-like domain (MC domain). The Mid domain can bind to the 5′ phosphate of single-stranded RNA by a divalent cation, and the PIWI domain catalyzes the activity of endoribonuclease (Hutvagner and Simard 2008). AGO1 is involved in the transcriptional suppression and cleavage of miRNAs, and this function is associated with the presence of miRNAs and AGO1 in polyribosomes (Brodersen et al. 2008; Lanet et al. 2009).
The double-stranded RNA binding protein complex DRB1/HYL1 participates in miRNA biogenesis by interacting with AGO1 and modulating strand selection through directional loading of the miRNA duplex into RISC for passenger strand degradation (Eamens et al. 2009). The molecular chaperone Hsp90 indirectly interferes with the function of RISC by interacting with AGO1 and altering its conformation. In addition, Hsp90 contains double-stranded RNA that binds to AGO1 and provides energy for the degradation of the RNA* in double-stranded RNA (Iki et al. 2010). In Arabidopsis, SQN, an orthologue of the immunophilin cyclophilin 40 (Cyp40), is involved in the silencing of miRNA. Many studies have found that SQN can interact with DCL1, HYL1, HEN1 and Hsp90, and works together with AGO1 to regulate the levels of miRNAs (Berardini et al. 2001; Smith et al. 2009). Enhanced MiRNA Active 1 (EMA1) and Transporter 1 (TRN1) encode two importin-β family proteins, which negatively and positively modulate the RISC loading process, respectively. The vast majority of miRNAs can be purified in the effector complex of miRNA in the ema1 mutants, implying that EMA1 regulates the activity of miRNAs by suppressing the loading of the miRNA into the AGO1 complex (Wang et al. 2011). In contrast to ema1, the trn1 mutant does not reduce the levels of miRNAs, but instead it deceases their activity. Furthermore, the trn1 mutant does not interfere with the distribution of miRNA and AGO1 in the nucleus and cytoplasm, but it inhibits the interaction between miRNAs and AGO1 (Wang et al. 2011; Cui et al. 2016).
Translational repression
Some miRNA target genes are regulated by miRNAs at the transcript level, while others only have translational alteration (Lanet et al. 2009). This protein translational repression primarily functions through ALTERED MEISTEM PROGRAM1 (AMP1), which can inhibit target mRNA entry into polyribosomes, while AMP1 is localized on the endoplasmic reticulum. Protein translation occurs at the rough endoplasmic reticulum surface, while both AGO1 and miRNAs are present in polyribosomes, which implies that the miRNA translational repression process takes place on the endoplasmic reticulum (Helliwell et al.2001; Li et al. 2013). In addition, there are other protein factors that regulate the miRNA-mediated translational repression. The SUO domain-containing GW protein can promote the translational repression of miRNAs and the microtubule-severing enzyme KATANIN1 (KTN1) also facilitates translational repression. Mutants in these genes have higher levels of target protein without altered levels of mRNA (Brodersen et al. 2008; Yang et al. 2012). DCP1, DCP2 and VCS co-localize into process bodies (P-bodies) and form a decapping complex in the cytoplasm, which is an important hub for the RISC complex to exercise its translational repression function (Xu et al. 2006; Brodersen et al. 2008).
Transcript cleavage
The RISC complex can inhibit gene expression through cleavage of the target mRNA. FBW2 is an inhibitor of AGO1 and the over-expression of FBW2 reduces the level of AGO1 protein but not AGO1 mRNA in Arabidopsis (Earley et al. 2010). Recently, CLF, which encodes a PRC2 methyltransferase complex, has been found to increase activity and stability of miRNA by preventing ubiquitination of AGO1. CLF directly regulates FBW2, which is a negative regulator of AGO1 (Earley et al. 2010; Ré et al. 2020). In Arabidopsis, HMG1 and HYDRA1 modulate the synthesis of isoprene, which regulates the formation of plant membrane proteins at the post-transcriptional level. Since AGO1 is a membrane protein, deletion of HMG1 can suppress the activity of miRNAs by reducing the formation of AGO1 (Brodersen et al. 2012). The Coenzyme factors RICE1 and RICE2 degrade the uridylation of cleavage targets, which are uridylated by HESO1 and UTR1 to regulate the function of the RISC (Zhang et al. 2017b). miRNAs play a significant role in plants, and function through RISC complex in the above two forms, and there are many regulatory mechanisms involved in its function to be explored.
Degradation of miRNAs
Studies have found that heso1-2 mutants can partially rescue hen1-2-induced miRNA reduction, which indicates that HESO1 is able to uridylate double-stranded miRNAs that are not methylated by HEN1, leading to higher levels of mature miRNAs (Ren et al. 2012b; Zhao et al. 2012). However, the presence of uridylated miRNA in both hen1 and heso1 mutants has been found, likely due to the fact that RNA uridine invertases URT1 and HESO1 can 3′ uridylate miRNAs methylated by HEN1. In addition, these proteins can independently perform their functions in multiple terminal nucleotide transferases at the 3′ tailing end of small RNAs and shift the balance between uridylation and trimming (Wang et al. 2015b). AGO1 colocalizes with autophagy-related protein 8a (ATG8a), demonstrating that the autophagy pathway of AGO1 also affects the stability of miRNAs (Derrien et al. 2012).
Other pathways participate in miRNA biogenesis
Epigenetic regulation of miRNA processing
Over the past decade, many studies have revealed the influence of epigenetic modifications on gene expression. Unsurprisingly, miRNA genes have also been shown to be regulated through similar epigenetic mechanisms in both plants and animals. In plants, the histone acetyltransferase General control non-repressed protein 5 (GCN5) can acetylate the H3K14 locus (Grant et al. 1997; Zhang et al. 2008). The acetylation of histones can also promote the transcription of miRNA genes, while the histone acetylation (HDAC) inhibitor TSA can reduce the accumulation of some miRNAs. In addition, the mutants of gcn5 cause increased expression of DCL1, SE, HYL1 and AGO1, which accelerates miRNA processing. In general, the histone acetylation/deacetylation epigenetic mechanisms depend on GCN5 interfering with miRNA biogenesis at both the transcriptional and post-transcriptional levels (Tian and Chen 2011; Kim et al. 2009). Additionally, the PRC2 complex can suppress MIR156/157 at the transcriptional level by catalyzing H3K27me3, which is a major epigenetic silencing mechanism in plants (Zhang et al. 2007; Lafos et al. 2011). There are many epigenetic pathways that interfere with the formation of miRNA, such as BRAHMA (BRM), ARABIDOPSIS TRITHORAX7 (ATXR7) and ATP-dependent SWR1 chromatin remodeling complex (SWR1-C) (Xu et al. 2016, 2018).
Alternative splicing regulation of miRNA processing
Alternative splicing (AS) of pri-miRNAs has been reported to influence the processing of miRNA by reducing the cleavage efficiency of the DCL1 complex. Additionally, miRNA transcripts without introns can reduce the accumulation of their respective mature miRNAs (Bielewicz et al. 2013; Schwab et al. 2013). MAC7 in the MOS4-ASSOCIATE COMPLEX influences the ability of HYL1 to localize to dicing bodies and participate in the processing of miRNA. In addition, MAC plays a key role in the splicing of mRNA in animals but only acts to shear some genes in Arabidopsis. However, recent research has found that transcripts with retained introns are significantly accumulated in the mac mutant compared to Col-0, which indicates that MAC may interfere with the formation of miRNAs by controlling the alternative splicing of pre-miRNAs (Xu et al. 2012; Zhang et al. 2013b; Jia et al. 2017). Recently, two conserved disassembly factors of the intron-lariat spliceosome (ILs) complex, Increased Level of Polyploidy1-1D (ILP1) and NTC-Related protein 1 (NTR1), have been found to promote miRNA processing by forming a complex to co-regulate the alternative splicing of pri-miRNAs. In addition, ILP1 and NTR1 improve the transcriptional elongation of MIR genes and interact with DCL1 and SE proteins (Wang et al. 2019b).
Exonuclease regulation of miRNA processing
The SMALL RNA DEGRADING NUCLEASE (SDN) family encodes four 3′-to-5′ exonucleases that promote the degradation of miRNAs. Among them, SDN1 is also able to degrade miRNAs by effectively recognizing their methylation sites at 2′-O-terminal in the 3′-terminal. Subsequent studies have found that SDN1 and SDN2 can cause 3′ truncation of some miRNAs, and AGO10 can participate in the degradation of SDN1 and SDN2 transcripts through miRNA165/166 (Yu et al. 2017b).
The DEDDy type 3′-to-5′ nucleic acid exonuclease ATRM2 can degrade unmethylated miRNAs and miRNAs*, while ATRM2 interacts with AGO proteins to participate in the monitoring of unmethylated double-stranded miRNA/miRNA* during the initiation of RISC protein complex formation (Wang et al. 2017). Recent studies have found that the 5′-3′ nucleic acid exonucleases XRN2 and XRN3 can promote the cleavage of pre-miRNA and thus affect miRNA formation (You et al. 2019). RICE1 and RICE2 also act as 3′-5′ exoribonucleases which degrade single-stranded RNAs and thus affect the function of RISC (Zhang et al. 2017b).
Chloroplast-to-nucleus signaling regulation of miRNA processing
CUE1 is a transporter protein localized to the chloroplast, which can transport phosphoenolpyruvate (PEP) into the chloroplast and then metabolize tyrosine to eventually produce vitamin E. Further research has found that vitamin E can regulate the entry of the retrograde chloroplast signaling molecule 3′-phosphoadenosine 5′-phosphate (PAP) to the nucleus and inhibit the activity of the RNA exonuclease XRN2 in the nucleus (Fang et al. 2019). Recent studies have also found that FRY1, a chloroplast-localized protein, can prevent PAP from interfering with the cleavage activity of XRN2/3 (Kim and Arnim 2009; You et al. 2019).
Perspectives
In recent years, the regulatory network of miRNAs in plants has gradually become clearer, and the impact of these networks on plant growth and development are being explored. Future studies will likely find many additional genes which are involved in miRNA biogenesis and function, including potential interactors with the DCL complex. Besides the known proteins, what proteins are involved in the transcription of the MIR gene? What other proteins affect the function of the Dicer-like complex during posttranscriptional processing? In addition to the existing processing pathways, are there any other ways that can participate the miRNA biogenesis? Addressing these issues will lead to a deeper understanding of the miRNA production process and its impact on plant health.
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Acknowledgements
This work was supported by the Public Projects of Zhejiang Province (No. LGN19C150007), National Natural Science Foundation of China (No. 31701915) and (Grant No. 31872105), and start-up fund from Zhejiang Agriculture & Forestry University (2017FR006). We thank Gang Wu for his advices on our review.
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Gao, Z., Nie, J. & Wang, H. MicroRNA biogenesis in plant. Plant Growth Regul 93, 1–12 (2021). https://doi.org/10.1007/s10725-020-00654-9
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DOI: https://doi.org/10.1007/s10725-020-00654-9