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Long noncoding RNA:unveiling hidden layer of gene regulatory networks

Long noncoding RNA:unveiling hidden layer of gene regulatory networks

Eun-Deok Kim and Sibum Sung

Section of Molecular Cell and Developmental Biology,the Institute for Cellular and Molecular Biology,

the University of Texas at Austin,Austin,TX78712,USA

Long noncoding RNAs(lncRNAs)are increasingly recog-nized as functional regulatory components in eukaryotic gene regulation.Distinct classes of lncRNAs have been identi?ed in eukaryotes and they play roles in various regulatory networks.Previously characterized lncRNAs include primary transcripts for small regulatory RNAs.In the era of deep sequencing,new classes of lncRNAs have emerged as potent regulatory components in gene reg-ulation.Recent studies showed that many lncRNAs are potent cis-and trans-regulators of gene activity and they can function as scaffolds for chromatin-modifying com-plexes.Furthermore,differential expressions of lncRNAs suggest that transcription of lncRNAs can modulate gene activity during development and in response to external stimuli.Here,we summarize our current under-standing on potential roles of lncRNAs in plants.

Long noncoding RNAs

Initial genome sequence analyses indicated that eukaryo-tic genomes include only a small percentage of protein-coding genes[1–3].In the model plant Arabidopsis (Arabidopsis thaliana),which has a relatively small genome,less than50%of its genome is capable of coding proteins[4].Thorough transcriptome analyses using deep sequencing and tiling arrays have revealed that up to 90%of eukaryotic genomes are transcribed into both protein-coding and non protein-coding RNAs,although as little as1–2%of them has protein coding capacity [1,2,5–7].In particular,an extraordinarily large number of transcripts with no apparent coding capacity has been identi?ed,dubbed as‘dark matter’of the genome[4,8]. These noncoding RNAs(ncRNAs)comprise a diverse group of transcripts.They include not only‘housekeeping’ncRNAs(ribosomal RNAs,transfer RNAs,small nuclear RNAs and small nucleolar RNAs),but also‘regulatory’ncRNAs.Earlier attention was given to small regulatory RNAs,such as micro RNAs(miRNAs)and small interfer-ing RNAs(siRNAs),as they play important roles in post-transcriptional and transcriptional regulations in eukaryotes.More recent studies of regulatory RNAs recog-nized a large number of long transcripts,so-called long noncoding RNAs(lncRNAs).Growing numbers of regula-tory lncRNAs are being recognized and shown to function in virtually every aspect of biology in eukaryotes.

The term of lncRNAs was introduced to distinguish them from well-known small regulatory RNAs(i.e.miRNAs and siRNAs)that are less than200nucleotides in general. Although the cutoff is arbitrary,longer than200nucleotide ncRNAs are generally considered as lncRNAs[2,9,10].Sev-eral lncRNAs have been known for decades,but it is not until recently that lncRNAs have emerged as potent regulators. Classic regulatory lncRNAs include Xist(X-inactive speci?c transcript),Air and Kcnq1ot1from mammals,and they are required for various epigenetic regulations of gene expres-sion[11–13].As exempli?ed from Tsix and RepA ncRNAs in X-chromosome inactivation(X inactivation),some lncRNAs act in cis to function through recruitment of chromatin-modifying complexes[13].Some long intergenic ncRNAs (lincRNAs),including p53-activated lincRNA-p21,target silencing activity to multiple genes located throughout the genome[14].Thus lincRNA-p21is a trans-acting down-stream repressor of multiple genes in the p53pathway[14]. Therefore,lncRNAs can act both in cis and/or trans to modulate gene activity of their target loci.Another impor-tant emerging theme is the ability of lncRNAs to bind chromatin-modifying complexes[15,16].RNA immuno-precipitation of PRC2or other chromatin-modifying factors identi?ed numerous lncRNAs and some of them have been shown to function in concert with chromatin-modifying complexes[15–18].

In plants,similar lncRNAs have been reported to function in directing chromatin-modifying activities to their targets and play an important role in development, such as?owering[19–22].Some lncRNAs appear to be very well conserved among eukaryotes,whereas others are plant speci?c.For example plant-speci?c RNA PO-LYMERASE V(Pol V)generates a distinct group of lncRNAs that is required for RNA-directed DNA meth-ylation(RdDM)[23–26],comprising of another class of regulatory lncRNAs compared to the classic regulatory lncRNAs.Based on several new discoveries associated with lncRNAs,we discuss the roles of regulatory lncRNAs in plants.While focusing on lncRNAs in plants, we also describe various lncRNAs in other organisms and their underlying mechanisms.

Types of long noncoding RNAs in plants

LncRNAs can originate from any location throughout the genome.Some lncRNAs are transcribed from introns or intergenic regions,and others overlap with protein-coding regions.They can be in either sense or antisense direction compared to neighboring protein-coding transcripts and also can overlap with exons and/or introns of protein-coding genes.

Review

Corresponding author:Sung,S.(sbsung@https://www.sodocs.net/doc/c7369141.html,).

161360-1385/$–see front matter?2011Elsevier Ltd.All rights reserved.doi:10.1016/j.tplants.2011.10.008Trends in Plant Science,January2012,Vol.17,No.1

Some lncRNAs are produced as primary transcripts which mature as small regulatory RNAs (Figure 1).For example,MIRNA genes encode longer transcripts (primary miRNAs)and primary miRNA transcripts are further processed to mature miRNAs [27,28].MIRNA genes are transcribed by RNA POLYMERASE II (Pol II),similar to protein-coding genes [28,29].In vertebrates and ?ies,most small regulatory RNAs are miRNAs [30].By contrast,miRNAs are minor constituents in small regulatory RNA population in plants which have relatively large and complex small regulatory RNA pools [27].The com-plexity of small RNA pools in plants is partly due to the presence of plant-speci?c RNA POLYMERASE IV/V (Pol IV/Pol V)-dependent siRNAs and secondary endogenous siRNAs [31–34].The Pol IV/Pol V-dependent siRNA bio-genesis pathway also includes productions of lncRNAs by Pol V and Pol V-dependent lncRNAs comprised of plant-speci?c class of lncRNAs,which are required for RdDM [23,35–38].

Natural antisense transcripts (NATs)are noncoding complementary transcripts of protein-coding transcripts.They are partly overlapped with sense transcripts.Recent studies showed that NATs represent a signi?cant portion of the transcriptome [39–41].Some NATs are transcribed in cis from the reverse strand of sense transcript-coding regions (cis -NAT)and others are transcribed in trans from different genomic loci (trans -NAT).A large number of NATs have been identi?ed from many plant species includ-ing Arabidopsis ,rice (Oryza sativa )and maize (Zea mays )[39–41].Some NATs apparently can form double-stranded RNAs,which in turn can serve as templates to generate endogenous siRNA,cis -nat -siRNA [42,43].Resulting en-dogenous siRNAs trigger heterochromatin formation at its target loci,establishing transcriptional silencing [44,45].In mammals,large sets of lncRNAs that are not pre-cursors of small RNAs have been identi?ed by deep se-quencing and tiling arrays [9].These lncRNAs regulate gene expression by a range of mechanisms,including mediating chromatin-modifying activity (Figure 1).In Arabidopsis ,a similar lncRNA,COLDAIR,mediates

epigenetic silencing of the ?oral repressor,FLOWERING LOCUS C (FLC )through directing chromatin modi?ca-tions [22].Roles of this class of lncRNAs are not restricted to gene repression.Some lncRNAs have shown to be asso-ciated with gene activation as well [46,47].Although lncRNAs are transcribed from anywhere in the genome,spatially and temporarily differential expressions of many lncRNAs suggest that they may play important roles in developmental programs in eukaryotes.

Scaffold for the RdDM pathway:atypical Pol V-dependent transcripts

Plants have two additional RNA polymerases –Pol IV and Pol V.Pol IV and Pol V are structurally and functionally distinct plant-speci?c RNA polymerases,although they contain Pol II-like subunit compositions,implying that Pol IV and Pol V share a common ancestor with Pol II [34].Unlike Pol II,they are not essential for viability in Arabidopsis [35,48].Instead,Pol IV is required for most endogenous siRNA production [32,36].Most heterochro-matic 24-nucleotide siRNAs depend on the presence of Pol IV in Arabidopsis [36].However,Pol V is not required for 24-nucleotide siRNAs at most loci,but is required for RdDM,which is a downstream event triggered by 24-nucleotide siRNAs [33,35,36].Although transcripts generated by Pol IV remain elusive,Pol V apparently generates lncRNAs from overlapping and adjacent regions of RdDM target loci [23,24].

Pol V-dependent lncRNAs are capped at 50-end,but lack apparent poly A tails [23].Pol V-dependent lncRNAs serve as scaffolds for siRNA-bound ARGONAUTE4(AGO4)(Figure 2a)[23].AGO4physically interacts with Pol V [24,49,50]and Pol V-dependent lncRNAs bind to AGO4,presumably through base-pairing between Pol V-dependent lncRNA and siRNA in AGO4[24].Thus Pol V-dependent lncRNAs function to recruit AGO4-associated silencing machinery to Pol V transcribed loci (Figure 2a).AGO4-associated silencing machinery includes RDM1(REQUIRED FOR DNA METHYLATION 1)and DRM2(DOMAINS REARRANGED METHYLTRANSERASE 2)

Pol II or Pol V Pol

Long noncoding RNA

Small RNA

Coding transcripts

Coding transcripts

or

or TRENDS in Plant Science

(i)

(ii)

(iii)

(iv)

Figure 1.Representative model for the roles of lncRNAs.(i)Some lncRNAs are precursors of small regulatory RNA.(ii)LncRNAs can serve as a scaffold for multiple protein complexes.(iii)Some lncRNAs act to trigger epigenetic changes by coordinating chromatin remodeling activity to their cis -linked target loci.(iv)Other lncRNAs can act on target loci in trans .

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and other chromatin modi?ers to establish de novo DNA methylation and chromatin modi?cations [51–54].Although it appears that Pol V-dependent lncRNAs may also be used to trigger secondary siRNA ampli?cations by AGOs,they apparently serve as scaffold to bring components required for RdDM to target loci in Arabidopsis [23].

Natural antisense transcripts

Some NATs provide the source for siRNA biogenesis in plants [42,43].However,there are NATs that do not over-lap with sites for siRNA production [39].Some evidence indicates that NATs may function to affect gene expression in cis independent of siRNA-mediated pathways [39].One such example came from the identi?cation of antisense RNAs from FLC [19,20].A group of NATs are transcribed from FLC and can be roughly grouped as class I and class II antisense transcripts based on their 30-end locations [20,21].The autonomous ?oral promotion pathway pro-teins act to repress FLC and include several RNA binding proteins,such as FCA and FPA.FCA and FPA appear to function to process the antisense transcripts at the proxi-mal 30-end and mutations in fca or fpa result in the increased amount of the antisense transcripts with the distal 30-end.A current proposed mechanism suggests that the proximal 30-end processing by FCA and FPA triggers the recruitment of histone H3Lys 4demethylase,FLD (another autonomous-pathway protein),and results in FLC repression [20].This proposed mechanism in which co-transcriptional processing of antisense lncRNAs is linked to chromatin modi?cations is a rather unique mech-anism that has not been found in other organisms.

Exposure to prolonged period of cold,also triggers the silencing of FLC ,through a process known as vernalization [55].The vernalization pathway functions to repress FLC in parallel with the autonomous pathway,i.e.mutations in the autonomous-pathway genes do not compromise the vernalization-mediated FLC silencing.The expression levels of some FLC antisense transcripts are transiently increased by vernalizing cold exposure [19].The cold-induced nature of the FLC antisense transcripts led to a speculation on the putative role of the antisense tran-scripts in vernalization-mediated FLC silencing.In hu-man,HOTAIR lncRNA acts as scaffold to recruit Polycomb Repression Complex 2(PRC2)to its targets.The cold-induced antisense transcripts,named COOLAIR,were proposed to be equivalents of HOTAIR lncRNA [56].However,a recent study showed that abolishment of COOLAIR antisense transcripts does not compromise ver-nalization-mediated FLC silencing [57].This indicates that cold-induced nature of COOLAIR antisense tran-scripts is perhaps a coincidence.Although many NATs have been identi?ed with interesting expression patterns in plants [58],the functionality of such NATs needs to be directly experimentally addressed.

Modulating chromatin-modifying activity:COLDAIR The role of the vernalization pathway is to repress expres-sion of a potent ?oral repressor,FLC ,after a suf?cient period of winter cold has been perceived.Following winter,the lack of FLC expression allows unimpeded operation of the photoperiod pathway and hence rapid ?owering of vernalized plants in spring via the activation of ?oral

Gene

IGR

Pol V

A? Cap

Pol V

AGO4

AGO4-RIST

Methylated siRNA

Pol V transcripts

Gene

IGR

Pol V

P o l

V t r a n s c r i p t s

FLC

TAG

Pol II

COLDAIR

ATG

Pol II

PRC2

TAG

Gene FLC

PRC2

ATG

5′ Cap

CH 3 CH 3 C H 3 CH 3 CH 3 C H 3

A G O 4

Figure 2.Schematic representations of biogenesis and function of two types of regulatory lncRNAs in plants.(a)Pol V-dependent lncRNAs (blue)is transcribing from

intergenic noncoding region (IGN).Transcribed Pol V-dependent lncRNAs physically interacts with AGO4-RISC (RNA-induced silencing complex)through the base-pairing between the lncRNAs and siRNAs.Once AGO4-RISC is recruited to target loci in part by physical interaction with Pol V-lncRNAs,subsequent changes ensue at their target loci,including de novo DNA methylation and chromatin modifications.(b)During the course of vernalization,an lncRNA,COLDAIR is transcribed from the first intron of FLC .COLDAIR physically interacts with PRC2and is required for the enrichment of PRC2at FLC chromatin by vernalization.Enrichment of PRC2at FLC is necessary to establish the stable repression of FLC .

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integrator genes.A key event in vernalization-mediated FLC silencing is the establishment of stable changes at FLC chromatin by the recruitments of chromatin-modifying complexes during cold exposure.Molecular studies showed that regulation of FLC is under the control of the interplay between Polycomb group(PcG)-mediated repression[59,60]and Trithorax group(TrxG)-mediated activation[61–65].On–off switching state of genes by PcG and TrxG is an evolutionarily conserved mechanism to coordinate cellular identity in eukaryotes[66,67].

PRC2is an evolutionarily conserved histone-modifying complex,that mediates histone H3Lys27methylation (H3K27me)in eukaryotes[68].In humans,the lncRNA HOTAIR is required for increased enrichment of PRC2at target loci[56,69].Knockdown of HOTAIR results in de-creased PRC2enrichment and thus reduced H3K27me at the HOXD cluster[56],illustrating the role of an lncRNA in modulating chromatin-modifying activity.HOTAIR act as scaffold for multiple chromatin-modifying complexes to orchestrate gene activity in developmental programs [17,18].In vernalization,increased enrichment of PRC2 at FLC by vernalization is an important step to establish mitotically stable silencing of FLC[55].A cold-induced lncRNA,COLDAIR,was identi?ed from the unusually large?rst intron of FLC[22].The?rst intron of FLC was previously proposed to contain a‘vernalization respon-sive element’as various deletions within the?rst intron impair stable FLC repression by vernalization[70,71]. Indeed,a previously identi?ed region to be important for the stable silencing of FLC by vernalization overlaps with the COLDAIR lncRNA promoter[71].

COLDAIR is a1.1-kb long lncRNAs.It is50-capped but does not have a30poly A tail similar to Pol V-dependent lncRNAs[22].However,mutations in either Pol IV or Pol V do not affect COLDAIR transcription and thus COLDAIR is not transcribed by Pol V.Instead,COLDAIR appears to be transcribed by Pol II,as transient increase of Pol II enrichment at the COLDAIR promoter is observed when COLDAIR is induced by cold[22].One criterion to deter-mine the functionality of lncRNAs as scaffold for chromatin-modifying complexes is to determine whether they physi-cally interact with chromatin-modifying complex compo-nents[46,72].Indeed,COLDAIR is associated with PRC2 both in vitro and in vivo.Furthermore,knockdown of COLDAIR using RNAi compromises the vernalization response in Arabidopsis.In particular,COLDAIR knock-down results in unstable silencing of FLC by vernalization, consistent with its role in the PRC2recruitment to FLC upon vernalization.Repression of FLC still occurs during cold exposure both in COLDAIR knockdown lines and in PRC2component mutants[22].However,FLC is de-repressed once plants are moved to warm growth tempera-tures both in COLDAIR knockdown lines and in PRC2 component mutants.In addition,increased PRC2enrich-ment at FLC by vernalization is largely impaired in COL-DAIR knockdown lines.Taken together,COLDAIR appears to be an equivalent of HOTAIR and both lncRNAs function to direct PRC2activity to their targets(Figure2b).The involvement of lncRNAs in PcG-mediated gene repression is likely an evolutionarily conserved mechanism between animals and plants.

Both Pol V-dependent lncRNAs and COLDAIR act to recruit components to trigger subsequent epigenetic changes at their origins(Figure2)[22,23].In the case of Pol V-dependent lncRNAs,target recognition is through base-pairing between siRNA and lncRNAs[24].siRNA is bound to AGO proteins and AGO proteins interact with a group of protein components required for DNA methyla-tion and chromatin modi?cations[24].PRC2-associated lncRNAs,such as HOTAIR,may recognize targets by DNA-RNA recognition.Although there is no experimental veri?cation of target-recognition mechanisms,genome-wide analysis of HOTAIR targets showed the existence of consensus sequences both in the lncRNA and their target DNAs[17],consistent with a DNA–RNA recognition mode for targeting.It remains to be determined whether COLDAIR is part of a DNA–RNA recognition system to direct PRC2activity to FLC.

A recent study in X inactivation showed that the Xist lncRNA can bind both PRC2and a DNA-binding protein, YY1[73].YY1recruits PRC2to the initial nucleation site by providing a bridge between lncRNA and DNA target sequences[73].Thus the interaction between lncRNA and DNA-binding protein can be used as a target-recognition mechanism.Although it is not known whether HOTAIR interacts with a DNA-binding protein,HOTAIR interacts with another chromatin-modifying complex,LSD1(His-tone H3Lys4demethylase)-containing complex[17]to coordinate multiple chromatin-modifying activities at its targets.It is yet to be determined whether COLDAIR can be a scaffold for other chromatin-modifying complexes and/ or DNA-binding proteins.

Other lncRNAs in plants

Some lncRNAs also affect the processing of small regula-tory RNAs by a target mimicry mechanism[74,75].The lncRNA,INDUCED BY PHOSPHATE STARVATIONA (IPS1),is a noncoding transcript that is intimately associ-ated with the function of miRNA399[76].Under phosphate starvation,the expression PHO2,a target of miRNA399,is up-regulated due to increased binding and sequestering of miRNA399by IPS1[76].IPS1contains complementary sequences to the phosphate(Pi)starvation-induced miRNA399and thus can compete with PHO2transcripts for the binding of miRNA399.However,IPS1is not cleaved by the miRNA because the paring with miRNA is inter-rupted by a mismatched loop at the expected miRNA cleavage site.Therefore,IPS1is a stable competitor and inhibits recycling of the miRNA effectors complex and sequestering miRNA.The mimic region of IPS1is highly conserved across many plant species,suggesting the con-served role of IPS1lncRNA in plants[74,77–79]. Perspectives

A recent?urry of papers describing roles of lncRNAs in various biological processes clearly demonstrates the poten-tial roles of lncRNAs as important regulators in many gene regulatory networks.The conformational versatility of RNA allows lncRNAs to form‘protein-like’structures.In many cases,nucleotide sequences of lncRNAs are not well con-served among related species[16].Rather,secondary struc-tures formed by lncRNAs appear to be conserved,i.e.‘double

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stem-and-loop’structure for PRC2binding[80–82].It is conceivable that lncRNAs can function similar to proteins through their conformational versatility to form various secondary structures.Furthermore,the innate base-pairing ability of RNAs illustrates their potential to function as DNA/RNA binding molecules.Aided by advances in deep sequencing technology,we expect to see more lncRNAs identi?ed from plants in the next few years.To date there are other classes of lncRNAs identi?ed in mammals,but not from plants.These include enhancer-associated RNAs,pro-moter-associated RNAs and a lncRNA that modulates TrxG-mediated gene activation[46,83,84].Challenges will be to distinguish regulatory lncRNAs from transcriptional noise. It is likely,however,that molecular understanding of the role of lncRNAs will shed light on this‘dark matter’in the genome as an important layer in gene regulatory network in many eukaryotes.

Acknowledgement

Sung Lab is supported by grants from the National Science Foundation and USDA.

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