The Arabidopsis PHD-finger protein EDM2 has multiple roles in balancing NLR immune receptor gene expression
Autoři:
Yan Lai aff001; Xueqing Maggie Lu aff003; Josquin Daron aff004; Songqin Pan aff001; Jianqiang Wang aff001; Wei Wang aff005; Tokuji Tsuchiya aff006; Eric Holub aff007; John M. McDowell aff005; R. Keith Slotkin aff004; Karine G. Le Roch aff003; Thomas Eulgem aff001
Působiště autorů:
Center for Plant Cell Biology, Institute of Integrative Genome Biology, Department of Botany and Plan Sciences, University of California at Riverside, Riverside, CA, United States of America
aff001; College of Life Sciences, Fujian Agricultural and Forestry University, Fuzhou, Fujian, China
aff002; Center for Infectious Disease and Vector Research, Institute of Integrative Genome Biology, Department of Molecular, Cell and Systems Biology, University of California at Riverside, Riverside, CA, United States of America
aff003; Department of Molecular Genetics, The Ohio State University, Columbus, Ohio, United States of America
aff004; Department of Plant Pathology, Physiology, and Weed Science, Virginia Tech, Blacksburg, VA, United States of America
aff005; College of Bioresource Sciences, Nihon University, Kanagawa, Japan
aff006; School of Life Sciences, University of Warwick, Wellesbourne campus, United Kingdom
aff007; Donald Danforth Plant Science Center, St. Louis, Missouri, United States of America
aff008; Division of Biological Sciences, University of Missouri, Columbia, Missouri, United States of America
aff009
Vyšlo v časopise:
The Arabidopsis PHD-finger protein EDM2 has multiple roles in balancing NLR immune receptor gene expression. PLoS Genet 16(9): e32767. doi:10.1371/journal.pgen.1008993
Kategorie:
Research Article
doi:
https://doi.org/10.1371/journal.pgen.1008993
Souhrn
Plant NLR-type receptors serve as sensitive triggers of host immunity. Their expression has to be well-balanced, due to their interference with various cellular processes and dose-dependency of their defense-inducing activity. A genetic “arms race” with fast-evolving pathogenic microbes requires plants to constantly innovate their NLR repertoires. We previously showed that insertion of the COPIA-R7 retrotransposon into RPP7 co-opted the epigenetic transposon silencing signal H3K9me2 to a new function promoting expression of this Arabidopsis thaliana NLR gene. Recruitment of the histone binding protein EDM2 to COPIA-R7-associated H3K9me2 is required for optimal expression of RPP7. By profiling of genome-wide effects of EDM2, we now uncovered additional examples illustrating effects of transposons on NLR gene expression, strongly suggesting that these mobile elements can play critical roles in the rapid evolution of plant NLR genes by providing the “raw material” for gene expression mechanisms. We further found EDM2 to have a global role in NLR expression control. Besides serving as a positive regulator of RPP7 and a small number of other NLR genes, EDM2 acts as a suppressor of a multitude of additional NLR genes. We speculate that the dual functionality of EDM2 in NLR expression control arose from the need to compensate for fitness penalties caused by high expression of some NLR genes by suppression of others. Moreover, we are providing new insights into functional relationships of EDM2 with its interaction partner, the RNA binding protein EDM3/AIPP1, and its target gene IBM1, encoding an H3K9-demethylase.
Klíčová slova:
Arabidopsis thaliana – Gene expression – Gene regulation – Genetic loci – Genomics – Plant genomics – Polyadenylation – Retrotransposons
Zdroje
1. Jones JD, Vance RE, Dangl JL. Intracellular innate immune surveillance devices in plants and animals. Science. 2016;354(6316):aaf6395. doi: 10.1126/science.aaf6395 27934708.
2. Jacob F, Vernaldi S, Maekawa T. Evolution and conservation of plant NLR functions. Front Immunol. 2013;4:297. doi: 10.3389/fimmu.2013.00297 24093022.
3. Li F, Pignatta D, Bendix C, Brunkard JO, Cohn MM, Tung J, et al. MicroRNA regulation of plant innate immune receptors. Proc Natl Acad Sci U S A. 2012;109(5):1790–1795. doi: 10.1073/pnas.1118282109 22307647.
4. Lai Y, Eulgem T. Transcript-level expression control of plant NLR genes. Mol Plant Pathol. 2018;19(5):1267–1281. doi: 10.1111/mpp.12607 28834153.
5. Bieri S, Mauch S, Shen QH, Peart J, Devoto A, Casais C, et al. RAR1 positively controls steady state levels of barley MLA resistance proteins and enables sufficient MLA6 accumulation for effective resistance. Plant Cell. 2004;16(12):3480–3495. doi: 10.1105/tpc.104.026682 15548741.
6. Holt BF, 3rd, Belkhadir Y, Dangl JL. Antagonistic control of disease resistance protein stability in the plant immune system. Science. 2005;309(5736):929–932. doi: 10.1126/science.1109977 15976272.
7. Stokes TL, Kunkel BN, Richards EJ. Epigenetic variation in Arabidopsis disease resistance. Genes Dev. 2002;16(2):171–182. doi: 10.1101/gad.952102 11799061.
8. Li Y, Yang S, Yang H, Hua J. The TIR-NB-LRR gene SNC1 is regulated at the transcript level by multiple factors. Mol Plant Microbe Interact. 2007;20(11):1449–1456. doi: 10.1094/MPMI-20-11-1449 17977156.
9. Karasov TL, Chae E, Herman JJ, Bergelson J. Mechanisms to mitigate the trade-off between growth and defense. Plant Cell. 2017;29(4):666–680. doi: 10.1105/tpc.16.00931 28320784.
10. Mohr TJ, Mammarella ND, Hoff T, Woffenden BJ, Jelesko JG, McDowell JM. The Arabidopsis downy mildew resistance gene RPP8 is induced by pathogens and salicylic acid and is regulated by W box cis elements. Mol Plant Microbe Interact. 2010;23(10):1303–1315. doi: 10.1094/MPMI-01-10-0022 20831409.
11. Saucet SB, Ma Y, Sarris PF, Furzer OJ, Sohn KH, Jones JD. Two linked pairs of Arabidopsis TNL resistance genes independently confer recognition of bacterial effector AvrRps4. Nat Commun. 2015;6:6338. doi: 10.1038/ncomms7338 25744164.
12. Chae E, Tran DT, Weigel D. Cooperation and conflict in the plant immune system. PLoS Pathog. 2016;12(3):e1005452. doi: 10.1371/journal.ppat.1005452 26986469.
13. Zhang Y, Xia R, Kuang H, Meyers BC. The diversification of plant NBS-LRR defense genes directs the evolution of microRNAs that target them. Mol Biol Evol. 2016;33(10):2692–2705. doi: 10.1093/molbev/msw154 27512116.
14. Eulgem T, Tsuchiya T, Wang XJ, Beasley B, Cuzick A, Tor M, et al. EDM2 is required for RPP7-dependent disease resistance in Arabidopsis and affects RPP7 transcript levels. Plant J. 2007;49(5):829–839. doi: 10.1111/j.1365-313X.2006.02999.x 17253987.
15. Tsuchiya T, Eulgem T. The Arabidopsis defense component EDM2 affects the floral transition in an FLC-dependent manner. Plant J. 2010a;62(3):518–528. doi: 10.1111/j.1365-313X.2010.04169.x 20149132.
16. Lei M, La H, Lu K, Wang P, Miki D, Ren Z, et al. Arabidopsis EDM2 promotes IBM1 distal polyadenylation and regulates genome DNA methylation patterns. Proc Natl Acad Sci U S A. 2014;111(1):527–532. doi: 10.1073/pnas.1320106110 24248388.
17. Tsuchiya T, Eulgem T. EMSY-like genes are required for full RPP7-mediated race-specific immunity and basal defense in Arabidopsis. Mol Plant Microbe Interact. 2011;24(12):1573–1581. doi: 10.1094/MPMI-05-11-0123 21830950.
18. Tsuchiya T, Eulgem T. An alternative polyadenylation mechanism coopted to the Arabidopsis RPP7 gene through intronic retrotransposon domestication. Proc Natl Acad Sci U S A. 2013b;110(37):3535–3543. doi: 10.1073/pnas.1312545110 23940361.
19. Duan CG, Wang X, Zhang L, Xiong X, Zhang Z, Tang K, et al. A protein complex regulates RNA processing of intronic heterochromatin-containing genes in Arabidopsis. Proc Natl Acad Sci U S A. 2017;114(35):7377–7384. doi: 10.1073/pnas.1710683114 28808009.
20. Lai Y, Cuzick A, Lu XM, Wang J, Katiyar N, Tsuchiya T, et al. The Arabidopsis RRM domain protein EDM3 mediates race-specific disease resistance by controlling H3K9me2-dependent alternative polyadenylation of RPP7 immune receptor transcripts. Plant J. 2019;97:646–660. doi: 10.1111/tpj.14148 30407670.
21. Tsuchiya T, Eulgem T. Mutations in EDM2 selectively affect silencing states of transposons and induce plant developmental plasticity. Scientific Reports. 2013a;3:1701. doi: 10.1038/srep01701 23609044.
22. Tsuchiya T, Eulgem T. Co-option of EDM2 to distinct regulatory modules in Arabidopsis thaliana development. BMC Plant Biology. 2010b;10(1):203. doi: 10.1186/1471-2229-10-203 20840782.
23. Jirage D, Zhou N, Cooper B, Clarke JD, Dong X, Glazebrook J. Constitutive salicylic acid-dependent signaling in cpr1 and cpr6 mutants requires PAD4. Plant J. 2001;26(4):395–407. doi: 10.1046/j.1365-313x.2001.2641040.x 11439127.
24. Maleck K, Neuenschwander U, Cade RM, Dietrich RA, Dangl JL, Ryals JA. Isolation and characterization of broad-spectrum disease-resistant Arabidopsis mutants. Genetics. 2002;160(4):1661–1671. 11973319.
25. Law JA, Jacobsen SE. Establishing, maintaining and modifying DNA methylation patterns in plants and animals. Nat Rev Genet. 2010;11(3):204–220. doi: 10.1038/nrg2719 20142834.
26. Matzke MA, Mosher RA. RNA-directed DNA methylation: an epigenetic pathway of increasing complexity. Nat Rev Genet. 2014;15(6):394–408. doi: 10.1038/nrg3683 24805120.
27. Stroud H, Do T, Du J, Zhong X, Feng S, Johnson L, et al. Non-CG methylation patterns shape the epigenetic landscape in Arabidopsis. Nat Struct Mol Biol. 2014;21(1):64–72. doi: 10.1038/nsmb.2735 24336224.
28. Du J, Zhong X, Bernatavichute YV, Stroud H, Feng S, Caro E, et al. Dual binding of chromomethylase domains to H3K9me2-containing nucleosomes directs DNA methylation in plants. Cell. 2012;151(1):167–180. doi: 10.1016/j.cell.2012.07.034 23021223.
29. Dinesh-Kumar SP, Baker BJ. Alternatively spliced N resistance gene transcripts: their possible role in tobacco mosaic virus resistance. Proc Natl Acad Sci U S A. 2000;97:1908–1913. doi: 10.1073/pnas.020367497 10660679.
30. Kuang H, Padmanabhan C, Li F, Kamei A, Bhaskar PB, Ouyang S, et al. Identification of miniature inverted-repeat transposable elements (MITEs) and biogenesis of their siRNAs in the Solanaceae: new functional implications for MITEs. Genome Res. 2009;19(1):42–56. doi: 10.1101/gr.078196.108 19037014.
31. Hayashi K, Yoshida H. Refunctionalization of the ancient rice blast disease resistance gene Pit by the recruitment of a retrotransposon as a promoter. Plant J. 2009;57(3):413–425. doi: 10.1111/j.1365-313X.2008.03694.x 18808453.
32. Bernatavichute YV, Zhang X, Cokus S, Pellegrini M, Jacobsen SE. Genome-wide association of histone H3 lysine nine methylation with CHG DNA methylation in Arabidopsis thaliana. PLoS One. 2008;3(9):e3156. doi: 10.1371/journal.pone.0003156 18776934.
33. van der Biezen EA, Freddie CT, Kahn K, Parker JE, Jones JDG. Arabidopsis RPP4 is a member of the RPP5 multigene family of TIR-NB-LRR genes and confers downy mildew resistance through multiple signaling components. Plant J. 2002;29(4):439–451. doi: 10.1046/j.0960-7412.2001.01229.x 11846877.
34. Holub EB, Beynon JL, Ctute IR. Phenotypic and genotypic characterization of interactions between isolates of Peronospora parasitica and accessions of Arabidopsis thaliana. Mol Plant Microbe Interact. 1994;7(2):223–239. doi: 10.1094/MPMI-7-0223
35. Ebbs ML, Bender J. Locus-specific control of DNA methylation by the Arabidopsis SUVH5 histone methyltransferase. Plant Cell. 2006;18(5):1166–1176. doi: 10.1105/tpc.106.041400 16582009.
36. Kindgren P, Ard R, Ivanov M, Marquardt S. Transcriptional read-through of the long non-coding RNA SVALKA governs plant cold acclimation. Nat Commun. 2018;9(1):4561. doi: 10.1038/s41467-018-07010-6 30385760.
37. Sinapidou E, Williams K, Nott L, Bahkt S, Tor M, Crute I, et al. Two TIR:NB:LRR genes are required to specify resistance to Peronospora parasitica isolate Cala2 in Arabidopsis. Plant J. 2004;38(6):898–909. doi: 10.1111/j.1365-313X.2004.02099.x 15165183.
38. Cuzick A. Genetic characterisation of four genes in Arabidopsis required for a non-salicylate-dependent source of downy mildew resistance. Thesis, Imperial College of Biotechnology, Science and Medicine at Wye, University of London, UK. 2001.
39. Michelmore RW, Meyers BC. Clusters of resistance genes in plants evolve by divergent selection and a birth-and-death process. Genome Res. 1998;8:1113–1130. doi: 10.1101/gr.8.11.1113 9847076.
40. McDowell JM, Simon SA. Recent insights into R gene evolution. Mol Plant Pathol. 2006;7(5):437–448. doi: 10.1111/j.1364-3703.2006.00342.x 20507459.
41. Saze H, Shiraishi A, Miura A, Kakutani T. Control of genic DNA methylation by a jmjC domain-containing protein in Arabidopsis thaliana. Science. 2008;319(5862):462–465. doi: 10.1126/science.1150987 18218897.
42. Miura A, Nakamura M, Inagaki S, Kobayashi A, Saze H, Kakutani T. An Arabidopsis jmjC domain protein protects transcribed genes from DNA methylation at CHG sites. EMBO J. 2009;28(8):1078–1086. doi: 10.1038/emboj.2009.59 19262562.
43. Rigal M, Kevei Z, Pelissier T, Mathieu O. DNA methylation in an intron of the IBM1 histone demethylase gene stabilizes chromatin modification patterns. EMBO J. 2012;31(13):2981–2993. doi: 10.1038/emboj.2012.141 22580822.
44. Inagaki S, Miura-Kamio A, Nakamura Y, Lu F, Cui X, Cao X, et al. Autocatalytic differentiation of epigenetic modifications within the Arabidopsis genome. EMBO J. 2010;29(20):3496–3506. doi: 10.1038/emboj.2010.227 20834229.
45. Ji L, Jordan WT, Shi X, Hu L, He C, Schmitz RJ. TET-mediated epimutagenesis of the Arabidopsis thaliana methylome. Nat Commun. 2018;9(1):895. doi: 10.1038/s41467-018-03289-7 29497035.
46. Wang YH, Warren JT Jr. Mutations in retrotransposon AtCOPIA4 compromises resistance to Hyaloperonospora parasitica in Arabidopsis thaliana. Genet Mol Biol. 2010;33(1):135–140. doi: 10.1590/S1415-47572009005000099 21637617.
47. Deremetz A, Le Roux C, Idir Y, Brousse C, Agorio A, Gy I, et al. Antagonistic actions of FPA and IBM2 regulate transcript processing from genes containing heterochromatin. Plant Physiol. 2019;180(1):392–403. doi: 10.1104/pp.18.01106 30814131.
48. Cheng YT, Li YZ, Huang SA, Huang Y, Dong XN, Zhang YL, et al. Stability of plant immune-receptor resistance proteins is controlled by SKP1-CULLIN1-F-box (SCF)-mediated protein degradation. Proc Natl Acad Sci U S A. 2011;108(35):14694–14699. doi: 10.1073/pnas.1105685108 21873230.
49. Gou MY, Shi ZY, Zhu Y, Bao ZL, Wang GY, Hua J. The F-box protein CPR1/CPR30 negatively regulates R protein SNC1 accumulation. Plant J. 2012;69(3):411–420. doi: 10.1111/j.1365-313X.2011.04799.x 21967323.
50. Chan C, Zimmerli L. The histone demethylase IBM1 positively regulates Arabidopsis immunity by control of defense gene expression. Frontiers in Plant Science. 2019;10:1587. doi: 10.3389/fpls.2019.01587 31956325
51. Meyers BC, Kozik A, Griego A, Kuang H, Michelmore RW. Genome-wide analysis of NBS-LRR-encoding genes in Arabidopsis. Plant Cell. 2003;15(4):809–834. doi: 10.1105/tpc.009308 12671079.
52. Wei F, Wing RA, Wise RP. Genome dynamics and evolution of the Mla (powdery mildew) resistance locus in barley. Plant Cell. 2002;14(8):1903–1917. doi: 10.1105/tpc.002238 12172030.
53. Miyao A, Tanaka K, Murata K, Sawaki H, Takeda S, Abe K, et al. Target site specificity of the Tos17 retrotransposon shows a preference for insertion within genes and against insertion in retrotransposon-rich regions of the genome. Plant Cell. 2003;15(8):1771–1780. doi: 10.1105/tpc.012559 12897251.
54. Takahashi A, Hayashi N, Miyao A, Hirochika H. Unique features of the rice blast resistance Pish locus revealed by large scale retrotransposon-tagging. BMC Plant Biol. 2010;10:175. doi: 10.1186/1471-2229-10-175 20707904.
55. Noël L, Moores TL, van der Biezen EA, Parniske M, Daniels MJ, Parker JE, et al. Pronounced intraspecific haplotype divergence at the RPP5 complex disease resistance locus of Arabidopsis. Plant Cell. 1999;11:2099–2111. doi: 10.2307/3871012 10559437
56. Guo YL, Fitz J, Schneeberger K, Ossowski S, Cao J, Weigel D. Genome-wide comparison of nucleotide-binding site-leucine-rich repeat-encoding genes in Arabidopsis. Plant Physiol. 2011;157(2):757–769. doi: 10.1104/pp.111.181990 21810963.
57. Galindo-Gonzalez L, Mhiri C, Deyholos MK, Grandbastien MA. LTR-retrotransposons in plants: Engines of evolution. Gene. 2017;626:14–25. doi: 10.1016/j.gene.2017.04.051 28476688.
58. Zervudacki J, Yu A, Amesefe D, Wang JY, Drouaud J, Navarro L, et al. Transcriptional control and exploitation of an immune-responsive family of plant retrotransposons. Embo J. 2018;37(14):e98482. doi: 10.15252/embj.201798482 29871888.
59. Le TN, Schumann U, Smith NA, Tiwari S, Au PC, Zhu QH, et al. DNA demethylases target promoter transposable elements to positively regulate stress responsive genes in Arabidopsis. Genome Biol. 2014;15(9):458. doi: 10.1186/s13059-014-0458-3 25228471.
60. Grandbastien MA. LTR retrotransposons, handy hitchhikers of plant regulation and stress response. Biochim Biophys Acta. 2015;1849(4):403–416. doi: 10.1016/j.bbagrm.2014.07.017 25086340.
61. Casacuberta E, Gonzalez J. The impact of transposable elements in environmental adaptation. Mol Ecol. 2013;22(6):1503–1517. doi: 10.1111/mec.12170 23293987.
62. Yu A, Lepere G, Jay F, Wang J, Bapaume L, Wang Y, et al. Dynamics and biological relevance of DNA demethylation in Arabidopsis antibacterial defense. Proc Natl Acad Sci U S A. 2013;110(6):2389–2394. doi: 10.1073/pnas.1211757110 23335630.
63. Dong S, Raffaele S, Kamoun S. The two-speed genomes of filamentous pathogens: waltz with plants. Curr Opin Genet Dev. 2015;35:57–65. doi: 10.1016/j.gde.2015.09.001 26451981.
64. Spanu PD. The genomics of obligate (and nonobligate) biotrophs. Annu Rev Phytopathol. 2012;50:91–109. doi: 10.1146/annurev-phyto-081211-173024 22559067.
65. Zhai J, Jeong DH, De Paoli E, Park S, Rosen BD, Li Y, et al. MicroRNAs as master regulators of the plant NB-LRR defense gene family via the production of phased, trans-acting siRNAs. Genes Dev. 2011;25(23):2540–2553. doi: 10.1101/gad.177527.111 22156213.
66. Shivaprasad PV, Chen HM, Patel K, Bond DM, Santos BA, Baulcombe DC. A microRNA superfamily regulates nucleotide binding site-leucine-rich repeats and other mRNAs. Plant Cell. 2012;24(3):859–874. doi: 10.1105/tpc.111.095380 22408077.
67. Saze H, Kitayama J, Takashima K, Miura S, Harukawa Y, Ito T, et al. Mechanism for full-length RNA processing of Arabidopsis genes containing intragenic heterochromatin. Nat Commun. 2013;4:2301. doi: 10.1038/ncomms3301 23934508.
68. Wang X, Duan CG, Tang K, Wang B, Zhang H, Lei M, et al. RNA-binding protein regulates plant DNA methylation by controlling mRNA processing at the intronic heterochromatin-containing gene IBM1. Proc Natl Acad Sci U S A. 2013;110(38):15467–15472. doi: 10.1073/pnas.1315399110 24003136.
69. McDowell JM, Cuzick A, Can C, Beynon J, Dangl JL, Holub EB. Downy mildew (Peronospora parasitica) resistance genes in Arabidopsis vary in functional requirements for NDR1, EDS1, NPR1, and Salicylic Acid accumulation. Plant J. 2000;22(6):523–530. doi: 10.1046/j.1365-313x.2000.00771.x 10886772.
70. Li H, Durbin R. Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics. 2009;25(14):1754–1760. doi: 10.1093/bioinformatics/btp324 19451168.
71. Quinlan AR, Hall IM. BEDTools: a flexible suite of utilities for comparing genomic features. Bioinformatics. 2010;26(6):841–842. doi: 10.1093/bioinformatics/btq033 20110278.
72. Love MI, Huber W, Anders S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 2014;15(12):550. doi: 10.1186/s13059-014-0550-8 25516281
73. Kim D, Langmead B, Salzberg SL. HISAT: a fast spliced aligner with low memory requirements. Nat Methods. 2015;12(4):357–360. doi: 10.1038/nmeth.3317 25751142.
74. Robinson JT, Thorvaldsdottir H, Winckler W, Guttman M, Lander ES, Getz G, et al. Integrative genomics viewer. Nat Biotechnol. 2011;29(1):24–26. doi: 10.1038/nbt.1754 21221095.
75. Zhang CJ, Du X, Tang K, Yang ZL, Pan L, Zhu PP, et al. Arabidopsis AGDP1 links H3K9me2 to DNA methylation in heterochromatin. Nature Communications. 2018;9:4547. doi: 10.1038/s41467-018-06965-w 30382101.
76. Kawabe A, Hansson B, Hagenblad J, Forrest A, Charlesworth D. Centromere locations and associated chromosome rearrangements in Arabidopsis lyrata and A. thaliana. Genetics. 2006;173(3):1613–1619. doi: 10.1534/genetics.106.057182 16648590.
77. Katagiri F, Thilmony R, He SY. The Arabidopsis thaliana-pseudomonas syringae interaction. Arabidopsis Book. 2002;1:e0039. doi: 10.1199/tab.0039 22303207.
78. Zhu X, Li S, Pan S, Xin X, Gu Y. CSI1, PATROL1, and exocyst complex cooperate in delivery of cellulose synthase complexes to the plasma membrane. Proc Natl Acad Sci U S A. 2018;115(15):3578–3587. doi: 10.1073/pnas.1800182115 29581258.
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