Endogenous RNAi and adaptation to environment in C. elegans.

2012·0.26 MB·English

by  Grishok, Alla

COMMENTARY
Worm1:2,129–133;April/May/June2012;G2012LandesBioscience
Endogenous RNAi and adaptation to environment in C. elegans
Alla Grishok
DepartmentofBiochemistryandMolecularBiophysics;ColumbiaUniversity;NewYork,NYUSA
The contributions of short RNAs to defense mechanism against viruses and
the control of repetitive elements repetitive DNA elements. Later, it was
are well documented in animals and discoveredthatsomeRNAifactors,suchas
plants. Here, the role of endogenous thedsRNA-specificribonucleaseDicer,do
RNAi and AF10 homolog ZFP-1 in the have a role in development.7-9 This role
adaptation of C. elegans to the environ- was shown to be in the processing of the
ment is discussed. First, modulation of hairpinprecursorsoftheshortRNAslin-4
insulin signaling through regulation of andlet-7,7,8whichwereknowntoregulate
© 2012 Landes Bioscience.
Keywords: endogenous RNAi, siRNA, transcription of the PDK-1 kinase developmental timing.10,11 lin-4 and let-7
insulin signaling, PDK-1, lifespan, (Mansisidor et al., PLoS Genetics, 2011) were the first examples of a class of
oxidative stress, transcription, epigenetics is reviewed. Second, an siRNA-based endogenous RNAs derived from hairpin
natural selection model is proposed in precursors and named microRNAs
Abbreviations: dsRNA, double-stranded which variation in endogenous siRNA (miRNAs).12-14 It became evident that
RNA; endo-siRNA, endogenous short pools between individuals is subject to miRNAs are not the only endogenous
Do not distribute.
interfering RNA; ZFP-1, zinc finger natural selection similarly to DNA-based small RNAs in C. elegans15 with the
protein 1; AF10, acute lymphoblastic genetic variation. The value of C. elegans discovery of increasing numbers of endo-
leukemia 1-Fused gene from chromosome fortheresearchofsiRNA-basedepigenetic genous siRNAs (endo-siRNAs) similar to
10; RDE-4, RNAi deficient 4; PDK-1, variation and adaptation is highlighted. thesiRNAsgeneratedduringexperimental
3-phosphoinositide-dependent kinase 1; dsRNA treatment.15-20 Endo-siRNAs are
RdRP,RNA-dependentRNApolymerase; short interfering RNAs that are largely
PI3K, phosphatidylinositol 3-kinase; Introduction generated by RNA-dependent RNA poly-
PTEN, phosphatase and tensin homolog; merases(RdRP)andareperfectlyantisense
DAF-16, DAF-18, abnormal dauer RNA interference was discovered in to the sequences of thousands of coding
formation; SKN-1, skinhead; PPTR-1, C.elegansas a gene silencingphenomenon genes.15-20 Recent studies have identified
protein phosphatase 2A regulatory subunit; inducedbydouble-strandedRNA(dsRNA) endo-siRNAs perfectly complementary to
CSR-1,chromosome-segregationandRNAi that was introduced by injection or by the coding mRNAs in flies21-24 and mam-
deficient; WAGO, worm-specific AGO feeding of bacteria that express dsRNA.1,2 mals,25,26 which means that these short
(argonaute); NRDE, nuclear RNAi Shortly, RNAi was shown to exist in RNAs are not limited to organisms
defective; piRNA, piwi-interacting RNA organisms ranging from fission yeast to containingRdRPgenes,suchasC.elegans.
humansandtobesimilartothephenome- DespitetheprogressofRNAiresearchand
Submitted: 01/04/12
non of repetitive transgene silencing dis- the discovery of increasing numbers of
Revised: 01/24/12 coveredinplants.3,4Thetwomajorstepsin pathways regulated by microRNAs, our
the RNAi process are: (1) generation of understanding of the biological roles of
Accepted: 01/30/12
short21–30ntinterferingRNAs(siRNAs) RNAiprocessesmediatedbyendo-siRNAs
http://dx.doi.org/10.4161/worm.19538
and (2) targeting of specific cellular RNAs is limited.
Correspondenceto:AllaGrishok; bysiRNAscomplementarytothesetargets,
Email:[email protected]
resultingingenesilencingthroughavariety RDE-4 and ZFP-1 Regulate
ofdifferentmechanisms. Endo-siRNA Targets
Commentaryto:MansisidorAR,CecereG,
ThefirstmutantsdeficientintheRNAi
HoerschS,JensenMB,KawliT,KennedyLM,etal.
response, rde, did not have obvious Inordertofindgenespotentiallyregulated
AConservedPHDFingerProteinand
EndogenousRNAiModulateInsulinSignalingin developmental abnormalities.5,6 However, by endogenous RNAi, we conducted an
Caenorhabditiselegans.PLoSGenet2012;7: some of them exhibited mobilization of mRNA expression profiling study27 using
e1002299;PMID:21980302;http://dx.doi.org/10. transposons in the germline,5,6 a pheno- mutants that affect RNAi-induced trans-
1371/journal.pgen.1002299
typeconsistentwiththeviewofRNAiasa criptional gene silencing.28 We chose
www.landesbioscience.com Worm 129
loss-of-functionmutantsintwogenes:rde-4 and the activation of genes encoding Currently, mechanistic studies of the
andzfp-1,whicharepredictedtoactinthe proteins combating oxidative-stress components of the multiple RNAi path-
initiation of RNAi and downstream in the damage, such as superoxide dismutase,37 ways in C. elegans are conducted largely
pathway, respectively. RDE-4 is a dsRNA- are essential for fitness in unfavorable independently of investigations of their
binding protein and a component of the conditions. Since the gene expression biological roles. Many reports identify
DicercomplexrequiredforsiRNAproduc- signature in the rde-4 and zfp-1 mutants changes in the expression of endo-siRNA
tion.29 It acts upstream in the RNAi was the opposite of that favored during target genes in mutants deficient in endo-
pathway.30 ZFP-1 is a chromatin factor stress, it suggested that these mutants siRNA production.17,18,46-51 It is often
homologous to human AF1031 and may should be deficient in stress responses. assumed that specific phenotypes of RNAi
mediate the repressive effect of siRNAs Indeed,wefoundthemtobeshort-lived,32 mutants are due to the combined effect of
ontheirtargetgenesdirectly. consistent with previous reports,38,39 and misregulationofamultitudeoftargets.We
Ouranalysisrevealedthatzfp-1andrde- sensitive to oxidative stress (paraquat) and find that misregulation of just one gene,
4 mutant animals have strikingly similar pathogens (P. aeruginosa).32 pdk-1, fully explains the reduced lifespan
profilesofmisregulatedgenes;closeto250 AlthoughZFP-1andendogenousRNAi and stress sensitivity of rde-4 mutant
genes are commonly regulated by both factors inhibit a number of genes whose animals since rde-4; pdk-1 double mutants
zfp-1 and rde-4.27 This functional link regulation may contribute to increased are long-lived and stress resistant, like
between upstream and downstream RNAi fitness, we found that downregulation pdk-1(sa709).32 Therefore, it is important
factors indicated the possibility of a of the 3-phosphoinositide-dependent to conduct careful epistasis and/or rescue
significant role for RNAi-induced chro- kinase-1 (PDK-1)40 by ZFP-1 and experimentswhengeneexpressionchanges
matin silencing in the regulation of RDE-4 is most significant for the normal arethoughttocausespecificphenotypes.
© 2012 Landes Bioscience.
endogenous genes. Additional analysis of life span and stress resistance of The role of a dsRNA-binding protein
the microarray data further supported a C. elegans.32 Indeed, the short lifespan RDE-4 in exogenous RNAi is relatively
direct role for RDE-4 and ZFP-1 in the and increased stress sensitivityof the zfp-1 well understood: it is required for the
regulation of RNAi targets: several studies and rde-4 mutants is fully suppressed by generation of siRNAs.29,30,52 However, its
had reported the cloning of hundreds the loss-of-function mutation in pdk-1.32 contributiontoendogenoussiRNAproduc-
of endogenous siRNAs antisense to the PDK-1 is a conserved kinase activated in tion is not so clear, as it is not uniformly
Do not distribute.
protein coding genes,15,19,20 and we found response to insulin and phosphatidylino- required47,51 and seems to participate in
a statistically significant enrichment of sitol (PI3), whose major targets are AKT more than one pathway.48,50 We have
genes with siRNAs in the sets of genes kinases40 (Fig.1). In C. elegans, activation connected the biological phenotype of the
upregulated in zfp-1 (p value 10222) and of AKT-1/2 through the insulin-signaling
rde-4 (p value 10219) mutants, but not pathway leads to the phosphorylation and
among the downregulated genes.27 These inactivation of DAF-16/FOXO41,42 and
data strongly suggested that the genes SKN-1/Nrf,43thekeytranscriptionfactors
upregulated in the studied mutants may promoting stress response and longevity
representdirecttargetsrepressedbyRNAi. (Fig.1). Therefore, modulation of the
The downregulated genes might be insulin-signaling pathway has a large
affected by the mutations indirectly. The impact on the global transcription profile
genome-wide localization of ZFP-1 is of an organism. The best-known factor
consistentwith its directroleinnegatively antagonizinginsulinandPI3Ksignalingis
regulating endo-siRNA targets32 (Cecere the lipid phosphatase PTEN (DAF-18 in
et al., in preparation). C. elegans).44 In addition, a serine/threo-
nine protein phosphatase PPTR-1 has
Modulation of Insulin Signaling been shown recently to antagonize
by ZFP-1 and RDE-4 AKT-1 phosphorylation and activation45
(Fig.1). Our work demonstrates that
Functional analysis of genes misregulated transcriptional modulation of signal trans-
in the zfp-1 and rde-4 mutants revealed a duction components has a potential for
connection to stress response and longe- inducing significant biological effects as
vity. First, translation-related genes tar- well. The zfp-1 gene has been previously
getedbyendogenoussiRNAswerenotably identified as a direct target of DAF-16,38
Figure1.Insulin-signalingpathwayand
upregulated in rde-4 and zfp-1 mutant and we find that DAF-16 has a modest
itsmodulatorsinC.elegans(adaptedfrom
animals.27 Second, metabolic genes positive effect on zfp-1 expression.32 This Fig.2C,Mansisidoretal.,2011).Factors
expressed in the intestine, which promote connection suggests a possibility of a promotinglongevityandresistanceto
longevity and resistance to oxidative positive feed-forward loop, which can be oxidativestressareshowninmagentafont;
stress,33 were downregulated in the same induced in response to initial DAF-16 factorsrestrictingoxidativestressresponses
areshowninblue.
mutants.27,32 Inhibition of translation34-36 activation during stress (Fig.1).32
130 Worm Volume1Issue2
rde-4 null mutant to the regulation of the (1) background levels of endo-siRNAs support the variation in endo-siRNA
pdk-1 gene. endo-siRNAs targeting pdk-1 specific to virtually any gene; (2) the abundance or the variation in the com-
areveryunabundantandmostlycorrespond ability of endo-siRNAs to significantly position of endo-siRNA pools between
to the repeatelements present atthepdk-1 downregulate the expression of their individuals, our analysis of RNAi inheri-
promoter.32Repeat-derivedpromoterendo- corresponding gene; (3) heritability of tance noted a high degree of variation
siRNAs have been documented for many endo-siRNAs; (4) differences between between siblings inheriting RNAi
other genes expressed higher in the rde-4 individuals in the composition of endo- (Grishok 2001, thesis research). Instead
mutants.32Therefore,repetitiveelementsin siRNA pools. There are several lines of of a large number of F2 progeny being
promoters appear to be utilized for gene evidence supporting these predictions: affected moderately by RNAi, a relatively
expressionregulationandadaptiveresponses (1) Cloned endo-siRNAs correspond to small number of individuals demonstrated
in C. elegans similarly to several instances virtually every gene of C. elegans,16-18,48 a very high level of RNAi while others
knowninplants.53,54 although some genes have thousands of were virtually unaffected.
themandothersonlyafew.(2)Aninverse EpigeneticRNAi-basedmechanismsare
Endo-siRNAs and Epigenetic correlation between the amount of endo- notlikelytobelimitedtolowerorganisms
Inheritance of Fitness siRNA present and the mRNA expression and may be involved in the immune
level of the corresponding gene in escape and drug-resistance of malignant
Endogenous RNAi in C. elegans targets C. elegans has been reported.17,18,46-51 (3) tumors and in other cases where cells
both repetitive elements and euchromatic, RNAi is heritable in C. elegans30,56,57 and evolve to escape the action of therapeutic
often essential, genes.16,17,48 Is there gene characteristics oftheheritableRNAiagent agents. The revelation that the epigenome
expression regulation by endogenous are consistent with those of siRNAs.30 In in the form of short RNAs is capable of
© 2012 Landes Bioscience.
RNAi that is not connected to control of addition, inheritance of functional modulating the response of organisms to
repetitive elements? The WAGO system DrosophilapiRNAsspecificfortransposon environmental stress may help elucidate
of redundant Argonautes,17 as well as the sequences has been reported,58 and a new ways of adaptation to harsh environ-
specific nuclear RNAi pathway of NRDE connectionbetweenepigeneticinheritance ments, and C. elegans promises to be a
proteins,55 appear to mediate genome and sperm RNA exists in mice.59 (4) perfect model organism for future dis-
surveillance, while gene-specific endo- Although there is no direct evidence to coveries in this exciting field.
Do not distribute.
siRNAs largely exist in a complex with
CSR-1 Argonaute.16 Consistently, we find
that endo-siRNA target genes expressed
higher in the rde-4 and zfp-1 mutant
larvae27 mostly represent CSR-1 targets
(Cecere et al., in press).
Theinhibitionofgeneexpressionbyan
RNA interference mechanism is the epi-
genetic equivalent of a genetic mutation.
The existence of a large pool of endo-
genous short RNAs antisense to many
genes (CSR-1-bound)16 may provide a
background of random epigenetic muta-
tions present in individuals. If selective
pressure isappliedtoapopulationofsuch
organisms or cells, not only genetic, but
also epigenetic variation could be subject
to selection. Selection for epigenetic traits
is faster and is also more flexible since it
can be easily reversed.
I propose that siRNA molecules repre-
sent the effectors of epigenetic variation
and selection and that changes in siRNA
levels leading to corresponding changes in
gene expression can be modulated by the
environment to ensure maximum fitness
Figure2.ModelfortheadjustmentofendogenoussiRNApoolsandepigeneticgeneexpression
of the organism (Fig.2). regulationtoenvironmentalconditions.InpopulationIthereisastochasticproductionandbackground
ThemodeloutlinedinFigure2predicts variationinsiRNApoolstargetinggenes1,2and3.Inorganism/cellA,theexpressionofgene1is
several important features of siRNA-based reduced,inorganism/cellB,gene2is,inorganism/cellC,gene3is.Whentheenvironmentchanges
totheadvantageoforganism/cellB,itsprogenywilldominatetheensuingpopulationII.
epigenetic adaptation to the environment:
www.landesbioscience.com Worm 131
Acknowledgments
I would like to thank the members of my
laboratory for many stimulating discus-
sions. Work on this project is supported
by the NIH Director’s New Innovator
Award (1 DP2 OD006412-01) to A.G.
References 14. LeeRC,AmbrosV.AnextensiveclassofsmallRNAs 27. Grishok A, Hoersch S, Sharp PA. RNA interference
in Caenorhabditis elegans. Science 2001; 294:862-4; and retinoblastoma-related genes are required for
1. FireA,XuS,MontgomeryMK,KostasSA,DriverSE, PMID:11679672; http://dx.doi.org/10.1126/science. repression of endogenous siRNA targets in
MelloCC.Potentandspecificgeneticinterferenceby 1065329 Caenorhabditis elegans. Proc Natl Acad Sci U S A
double-stranded RNA in Caenorhabditis elegans. 15. AmbrosV,LeeRC,LavanwayA,WilliamsPT,Jewell 2008;105:20386-91;PMID:19073934;http://dx.doi.
Nature 1998; 391:806-11; PMID:9486653; http:// D.MicroRNAsandothertinyendogenousRNAsinC. org/10.1073/pnas.0810589105
dx.doi.org/10.1038/35888
elegans.CurrBiol2003;13:807-18;PMID:12747828; 28. Grishok A, Sinskey JL, Sharp PA. Transcriptional
2. TimmonsL,FireA.Specificinterferencebyingested http://dx.doi.org/10.1016/S0960-9822(03)00287-2 silencing of atransgenebyRNAi inthesomaofC.
dsRNA. Nature 1998; 395:854; PMID:9804418; 16. ClaycombJM,BatistaPJ,PangKM,GuW,VasaleJJ, elegans. Genes Dev 2005; 19:683-96; PMID:
http://dx.doi.org/10.1038/27579 vanWolfswinkelJC,etal.TheArgonauteCSR-1and 15741313;http://dx.doi.org/10.1101/gad.1247705
3. NapoliC,LemieuxC,JorgensenR.Introductionofa its 22G-RNA cofactors are required for holocentric 29. TabaraH,YigitE,SiomiH,MelloCC.ThedsRNA
ChimericChalconeSynthaseGeneintoPetuniaResults chromosome segregation. Cell 2009; 139:123-34; bindingproteinRDE-4interactswithRDE-1,DCR-1,
inReversibleCo-SuppressionofHomologousGenesin PMID:19804758; http://dx.doi.org/10.1016/j.cell. andaDExH-boxhelicasetodirectRNAiinC.elegans.
trans. Plant Cell 1990; 2:279-89; PMID:12354959; 2009.09.014 Cell 2002; 109:861-71; PMID:12110183; http://dx.
http://dx.doi.org/10.1105/tpc.2.4.279 17. GuW,ShirayamaM,ConteD,Jr.,VasaleJ,BatistaPJ, doi.org/10.1016/S0092-8674(02)00793-6
4. vanderKrolAR,MurLA,BeldM,MolJN,Stuitje ClaycombJM,etal.Distinctargonaute-mediated22G- 30. GrishokA,TabaraH,MelloCC.Geneticrequirements
AR.Flavonoidgenesinpetunia:additionofalimited RNA pathways direct genome surveillance in the C. forinheritanceofRNAiinC.elegans.Science2000;
©numbe r of2gene cop0iesmay1leadtoa2suppress ionLof aelegnansgermdline.MoelCell2s009;36 :23B1-44;PMiID:os287:249c4-7; PiMIDe:10741n970; httcp://dx.deoi.org/1.0.
gene expression. Plant Cell 1990; 2:291-9; PMID: 19800275; http://dx.doi.org/10.1016/j.molcel.2009. 1126/science.287.5462.2494
2152117 09.020 31. Dudley NR, Labbé JC, Goldstein B. Using RNA
5. KettingRF,HaverkampTH,vanLuenenHG,Plasterk 18. Han T, Manoharan AP, Harkins TT, Bouffard P, interference to identify genes required for RNA
RH. Mut-7 of C. elegans, required for transposon Fitzpatrick C, Chu DS, et al. 26G endo-siRNAs interference. Proc Natl Acad Sci U S A 2002;
silencing and RNA interference, is a homolog of regulatespermatogenicandzygoticgeneexpressionin 99:4191-6; PMID:11904378; http://dx.doi.org/10.
Werner syndrome helicase and RNaseD. Cell 1999; Caenorhabditis elegans. Proc Natl Acad Sci U S A 1073/pnas.062605199
99:133-41; PMID:10535732; http://dx.doi.org/10. 2009; 106:18674-9; PMID:19846761; http://dx.doi. 32. Mansisidor AR, Cecere G, Hoersch S, Jensen MB,
1016/S0092-8674(00)81645-1 org/10.1073/pnas.0906378106 KawliT,KennedyLM,etal.AconservedPHDfinger
6. TabaraH,SarkissianM,KelDlyWG,FloeenorJ,G risnhok o19. PaktJ, F ire dA. Distinict psopulatiotns orf primiaryband uprottein eand en.dogenous RNAi modulate insulin
A, Timmons L, et al. The rde-1 gene, RNA secondaryeffectorsduringRNAiinC.elegans.Science signaling in Caenorhabditis elegans. PLoS Genet
interference, and transposon silencing in C. elegans. 2007;315:241-4;PMID:17124291;http://dx.doi.org/ 2011; 7:e1002299; PMID:21980302; http://dx.doi.
Cell 1999; 99:123-32; PMID:10535731; http://dx. 10.1126/science.1132839 org/10.1371/journal.pgen.1002299
doi.org/10.1016/S0092-8674(00)81644-X
20. Ruby JG, Jan C, Player C, Axtell MJ, Lee W, 33. Murphy CT, McCarroll SA, Bargmann CI, Fraser A,
7. GrishokA,PasquinelliAE,ConteD,LiN,ParrishS, Nusbaum C, et al. Large-scale sequencing reveals KamathRS,AhringerJ,etal.Genesthatactdownstream
Ha I, et al. Genes and mechanisms related to RNA 21U-RNAs and additional microRNAs and endo- ofDAF-16toinfluencethelifespanofCaenorhabditis
interferenceregulateexpressionofthesmalltemporal genous siRNAs in C. elegans. Cell 2006; 127:1193- elegans. Nature 2003; 424:277-83; PMID:12845331;
RNAs that control C. elegans developmental timing. 207; PMID:17174894; http://dx.doi.org/10.1016/j. http://dx.doi.org/10.1038/nature01789
Cell 2001; 106:23-34; PMID:11461699; http://dx. cell.2006.10.040 34. Curran SP, Ruvkun G. Lifespan regulation by
doi.org/10.1016/S0092-8674(01)00431-7
21. CzechB,MaloneCD,ZhouR,StarkA,Schlingeheyde evolutionarily conserved genes essential for viability.
8. KettingRF,FischerSE,BernsteinE,SijenT,Hannon C, Dus M, et al. An endogenous small interfering PLoSGenet2007;3:e56;PMID:17411345;http://dx.
GJ,PlasterkRH.DicerfunctionsinRNAinterference RNA pathway in Drosophila. Nature 2008; 453: doi.org/10.1371/journal.pgen.0030056
and in synthesis of small RNA involved in develop- 798-802;PMID:18463631;http://dx.doi.org/10.1038/ 35. HansenM,TaubertS,CrawfordD,LibinaN,LeeSJ,
mental timing in C. elegans. Genes Dev 2001; nature07007 Kenyon C. Lifespan extension by conditions that
15:2654-9; PMID:11641272; http://dx.doi.org/10.
22. GhildiyalM,SeitzH,HorwichMD,LiC,DuT,Lee inhibit translation in Caenorhabditis elegans. Aging
1101/gad.927801
S,etal.EndogenoussiRNAsderivedfromtransposons Cell2007;6:95-110;PMID:17266679;http://dx.doi.
9. KnightSW,BassBL.ArolefortheRNaseIIIenzyme andmRNAsinDrosophilasomaticcells.Science2008; org/10.1111/j.1474-9726.2006.00267.x
DCR-1 in RNA interference and germ line develop- 320:1077-81; PMID:18403677; http://dx.doi.org/10. 36. SyntichakiP,TroulinakiK,TavernarakisN.eIF4Efunc-
ment in Caenorhabditis elegans. Science 2001; 1126/science.1157396 tioninsomaticcellsmodulatesageinginCaenorhabditis
293:2269-71; PMID:11486053; http://dx.doi.org/10.
23. Kawamura Y, Saito K, Kin T, Ono Y, Asai K, elegans. Nature 2007; 445:922-6; PMID:17277769;
1126/science.1062039
Sunohara T, et al. Drosophila endogenous small http://dx.doi.org/10.1038/nature05603
10. Lee RC, Feinbaum RL, Ambros V. The C. elegans RNAs bind to Argonaute 2 in somatic cells. Nature 37. FinkelT,HolbrookNJ.Oxidants,oxidativestressand
heterochronic gene lin-4 encodes small RNAs with 2008;453:793-7;PMID:18463636;http://dx.doi.org/ thebiologyofageing.Nature2000;408:239-47;PMID:
antisense complementarity to lin-14. Cell 1993; 10.1038/nature06938 11089981;http://dx.doi.org/10.1038/35041687
75:843-54; PMID:8252621; http://dx.doi.org/10.
24. OkamuraK,ChungWJ,RubyJG,GuoH,BartelDP, 38. OhSW,MukhopadhyayA,DixitBL,RahaT,Green
1016/0092-8674(93)90529-Y
Lai EC. The Drosophila hairpin RNA pathway MR,TissenbaumHA.IdentificationofdirectDAF-16
11. Reinhart BJ, Slack FJ, Basson M, Pasquinelli AE, generatesendogenousshortinterferingRNAs.Nature targetscontrollinglongevity,metabolismanddiapause
Bettinger JC, Rougvie AE, et al. The 21-nucleotide 2008;453:803-6;PMID:18463630;http://dx.doi.org/ bychromatinimmunoprecipitation.NatGenet2006;
let-7 RNA regulates developmental timing in 10.1038/nature07015 38:251-7; PMID:16380712; http://dx.doi.org/10.
Caenorhabditis elegans. Nature 2000; 403:901-6;
25. TamOH,AravinAA,SteinP,GirardA,Murchison 1038/ng1723
PMID:10706289;http://dx.doi.org/10.1038/35002607
EP, Cheloufi S, et al. Pseudogene-derived small 39. WelkerNC,HabigJW,BassBL.Genesmisregulated
12. Lagos-QuintanaM,RauhutR,LendeckelW,Tuschl interfering RNAs regulate gene expression in mouse inC.elegansdeficientinDicer,RDE-4,orRDE-1are
T. Identification of novel genes coding for small oocytes. Nature 2008; 453:534-8; PMID:18404147; enriched for innate immunity genes. RNA 2007;
expressed RNAs. Science 2001; 294:853-8; PMID: http://dx.doi.org/10.1038/nature06904 13:1090-102; PMID:17526642; http://dx.doi.org/10.
11679670;http://dx.doi.org/10.1126/science.1064921
26. Watanabe T, Totoki Y, Toyoda A, Kaneda M, 1261/rna.542107
13. Lau NC, Lim LP, Weinstein EG, Bartel DP. An Kuramochi-Miyagawa S, Obata Y, et al. Endogenous
abundantclassoftinyRNAswithprobableregulatory siRNAsfromnaturallyformeddsRNAsregulatetranscripts
roles in Caenorhabditis elegans. Science 2001; 294: in mouse oocytes. Nature 2008; 453:539-43; PMID:
858-62;PMID:11679671;http://dx.doi.org/10.1126/ 18404146;http://dx.doi.org/10.1038/nature06908
science.1065062
132 Worm Volume1Issue2
40. Paradis S, Ailion M, Toker A,Thomas JH, Ruvkun 47. Duchaine TF, Wohlschlegel JA, Kennedy S, Bei Y, 54. Agorio A, Vera P. ARGONAUTE4 is required for
GA.APDK1homologisnecessary andsufficientto Conte D, Jr., Pang K, et al. Functional proteomics resistance to Pseudomonas syringae in Arabidopsis.
transduce AGE-1 PI3 kinase signals that regulate revealsthebiochemicalnicheofC.elegansDCR-1in Plant Cell 2007; 19:3778-90; PMID:17993621;
diapauseinCaenorhabditiselegans.GenesDev1999; multiple small-RNA-mediated pathways. Cell 2006; http://dx.doi.org/10.1105/tpc.107.054494
13:1438-52; PMID:10364160; http://dx.doi.org/10. 124:343-54; PMID:16439208; http://dx.doi.org/10. 55. BurkhartKB,GuangS,BuckleyBA,WongL,Bochner
1101/gad.13.11.1438 1016/j.cell.2005.11.036 AF,KennedyS.Apre-mRNA-associatingfactorlinks
41. LinK,DormanJB,RodanA,KenyonC.daf-16:An 48. Maniar JM, Fire AZ. EGO-1, a C. elegans RdRP, endogenous siRNAs to chromatin regulation. PLoS
HNF-3/forkheadfamilymemberthatcanfunctionto modulatesgeneexpressionviaproductionofmRNA- Genet2011;7:e1002249;PMID:21901112;http://dx.
doublethelife-spanofCaenorhabditiselegans.Science templated short antisense RNAs. Curr Biol 2011; doi.org/10.1371/journal.pgen.1002249
1997; 278:1319-22; PMID:9360933; http://dx.doi. 21:449-59; PMID:21396820; http://dx.doi.org/10. 56. AlcazarRM,LinR,FireAZ.Transmissiondynamicsof
org/10.1126/science.278.5341.1319 1016/j.cub.2011.02.019 heritablesilencinginducedbydouble-strandedRNAin
42. Ogg S, Paradis S, Gottlieb S, Patterson GI, Lee L, 49. PavelecDM,LachowiecJ,DuchaineTF,SmithHE, Caenorhabditiselegans.Genetics2008;180:1275-88;
Tissenbaum HA, et al. The Fork head transcription KennedyS.RequirementfortheERI/DICERcomplex PMID:18757930; http://dx.doi.org/10.1534/genetics.
factor DAF-16 transduces insulin-like metabolic and inendogenousRNAinterferenceandspermdevelop- 108.089433
longevitysignalsinC.elegans.Nature1997;389:994- ment in Caenorhabditis elegans. Genetics 2009; 57. VastenhouwNL,BrunschwigK,OkiharaKL,Müller
9;PMID:9353126;http://dx.doi.org/10.1038/40194 183:1283-95; PMID:19797044; http://dx.doi.org/10. F,TijstermanM,PlasterkRH.Geneexpression:long-
43. TulletJM,HertweckM,AnJH,BakerJ,HwangJY, 1534/genetics.109.108134 termgenesilencingbyRNAi.Nature2006;442:882;
Liu S, et al. Direct inhibition of the longevity- 50. VasaleJJ,GuW,ThiviergeC,BatistaPJ,Claycomb PMID:16929289;http://dx.doi.org/10.1038/442882a
promoting factor SKN-1 by insulin-like signaling in JM,YoungmanEM,etal.SequentialroundsofRNA- 58. BrenneckeJ,MaloneCD,AravinAA,Sachidanandam
C.elegans.Cell2008;132:1025-38;PMID:18358814; dependentRNAtranscriptiondriveendogenoussmall- R, Stark A, Hannon GJ. An epigenetic role for
http://dx.doi.org/10.1016/j.cell.2008.01.030 RNAbiogenesisintheERGO-1/Argonautepathway. maternally inherited piRNAs in transposon silencing.
44. OggS,RuvkunG.TheC.elegans PTENhomolog, ProcNatlAcadSciUSA2010;107:3582-7;PMID: Science2008;322:1387-92;PMID:19039138;http://
DAF-18, acts in the insulin receptor-like metabolic 20133583;http://dx.doi.org/10.1073/pnas.0911908107 dx.doi.org/10.1126/science.1165171
signalingpathway.MolCell1998;2:887-93;PMID: 51. LeeRC, HammellCM, AmbrosV. Interacting endo- 59. RassoulzadeganM,GrandjeanV,GounonP,Vincent
9885576; http://dx.doi.org/10.1016/S1097-2765(00) genousandexogenousRNAipathwaysinCaenorhabditis S, Gillot I, Cuzin F. RNA-mediated non-mendelian
80303-2 elegans. RNA 2006; 12:589-97; PMID:16489184; inheritance of an epigenetic change in the mouse.
45. PadmanabhanS,MukhopadhyayA,NarasimhanSD, http://dx.doi.org/10.1261/rna.2231506 Nature 2006; 441:469-74; PMID:16724059; http://
©Tesz G , C2zech M0P, Tissen1baum H2AA. A PPL2A a52. ParnrishS,FidreA.DisteinctrolessforRD E-B1andRDiE-4osdx.doi.ocrg/10.1i038e/nature0n4674 ce.
regulatory subunit regulates C. elegans insulin/IGF-1 during RNA interference in Caenorhabditis elegans.
signalingbymodulatingAKT-1phosphorylation.Cell RNA2001;7:1397-402;PMID:11680844
2009; 136:939-51; PMID:19249087; http://dx.doi. 53. Chan SW, Zilberman D, Xie Z, Johansen LK,
org/10.1016/j.cell.2009.01.025 Carrington JC, Jacobsen SE. RNA silencing genes
46. ConineCC,BatistaPJ,GuW,ClaycombJM,Chaves control de novo DNA methylation. Science 2004;
DA,ShirayamaM,etal.ArgonautesALG-3andALG- 303:1336; PMID:14988555; http://dx.doi.org/10.
4arerequiredforspermatogenesis-specific26G-RNAs 1126/science.1095989
and thermotolerant sperm in Caenorhabditis elegans.
Do not distribute.
ProcNatlAcadSciUSA2010;107:3588-93;PMID:
20133686;http://dx.doi.org/10.1073/pnas.0911685107
www.landesbioscience.com Worm 133