Extensive RNA editing and splicing increase immune self-representation diversity in medullary thymic epithelial cells

Genome Biology

Volumn 17, Issue 1, 2016, Pages

  Danan Gotthold, Miri ^a   Guyon, Clotilde ^b   Giraud, Matthieu ^b   Levanon, Erez Y ^a   Abramson, Jakub ^c  

^a BAR ILAN UNIVERSITY   (Israel)

^b INSTITUT COCHIN   (France)

^c WEIZMANN INSTITUTE OF SCIENCE   (Israel)

Author keywords

Alternative splicing; Medullary thymic epithelial cells (mTECs); RNA editing; RNA sequencing; Self tolerance; Thymus

Indexed keywords

ALTERNATIVE RNA SPLICING; AUTOIMMUNITY; DNA TRANSCRIPTION; EPITHELIUM CELL; GENE EXPRESSION; IMMUNOLOGICAL TOLERANCE; MEDIATOR; PREVENTION; RNA EDITING; RNA SEQUENCE; THYMUS; TRANSCRIPTION REGULATION; ANIMAL; CELL DIFFERENTIATION; GENE EXPRESSION REGULATION; GENETICS; HUMAN; IMMUNOLOGY; MOUSE; T LYMPHOCYTE;

AUTOANTIGEN; TRANSCRIPTION FACTOR;

ALTERNATIVE SPLICING; ANIMALS; AUTOANTIGENS; CELL DIFFERENTIATION; EPITHELIAL CELLS; GENE EXPRESSION REGULATION; HUMANS; MICE; RNA EDITING; SELF TOLERANCE; T-LYMPHOCYTES; THYMUS GLAND; TRANSCRIPTION FACTORS;

EID: 84992316081     PISSN: 14747596     EISSN: 1474760X     Source Type: Journal    
DOI: 10.1186/s13059-016-1079-9     Document Type: Article

References (72)

1. Klein L, Kyewski B, Allen PM, Hogquist KA. Positive and negative selection of the T cell repertoire: what thymocytes see (and don't see). Nat Rev Immunol. 2014;14:377-91.
2. Derbinski J, Schulte A, Kyewski B, Klein L. Promiscuous gene expression in medullary thymic epithelial cells mirrors the peripheral self. Nat Immunol. 2001;2:1032-9.
3. Anderson MS, Venanzi ES, Klein L, Chen Z, Berzins SP, Turley SJ, et al. Projection of an immunological self shadow within the thymus by the aire protein. Science. 2002;298:1395-401.
4. Peterson P, Org T, Rebane A. Transcriptional regulation by AIRE: molecular mechanisms of central tolerance. Nat Rev Immunol. 2008;8:948-57.
5. Nagamine K, Peterson P, Scott HS, Kudoh J, Minoshima S, Heino M, et al. Positional cloning of the APECED gene. Nat Genet. 1997;17:393-8.
6. Graveley BR. Alternative splicing: increasing diversity in the proteomic world. Trends Genet. 2001;17:100-7.
7. Rosenthal JJC. The emerging role of RNA editing in plasticity. J Exp Biol. 2015;218(Pt 12):1812-21.
8. Pan Q, Shai O, Lee LJ, Frey BJ, Blencowe BJ. Deep surveying of alternative splicing complexity in the human transcriptome by high-throughput sequencing. Nat Genet. 2008;40:1413-5.
9. Wang ET, Sandberg R, Luo S, Khrebtukova I, Zhang L, Mayr C, et al. Alternative isoform regulation in human tissue transcriptomes. Nature. 2008;456:470-6.
10. Nilsen TW, Graveley BR. Expansion of the eukaryotic proteome by alternative splicing. Nature. 2010;463:457-63.
11. Stamm S, Ben-Ari S, Rafalska I, Tang Y, Zhang Z, Toiber D, et al. Function of alternative splicing. Gene. 2005;344:1-20.
12. Kelemen O, Convertini P, Zhang Z, Wen Y, Shen M, Falaleeva M, et al. Function of alternative splicing. Gene. 2013;514:1-30.
13. Kim E, Goren A, Ast G. Alternative splicing: current perspectives. Bioessays. 2008;30:38-47.
14. Nishikura K. Functions and regulation of RNA editing by ADAR deaminases. Annu Rev Biochem. 2010;79:321-49.
15. Savva YA, Rieder LE, Reenan RA. The ADAR protein family. Genome Biol. 2012;13:252.
16. Porath HT, Carmi S, Levanon EY. A genome-wide map of hyper-edited RNA reveals numerous new sites. Nat Commun. 2014;5:4726.
17. Burns CM, Chu H, Rueter SM, Hutchinson LK, Canton H, Sanders-Bush E, et al. Regulation of serotonin-2C receptor G-protein coupling by RNA editing. Nature. 1997;387:303-8.
18. Ramaswami G, Li JB. RADAR: a rigorously annotated database of A-to-I RNA editing. Nucleic Acids Res. 2014;42:D109-13.
19. Danecek P, Nellåker C, McIntyre RE, Buendia-Buendia JE, Bumpstead S, Ponting CP, et al. High levels of RNA-editing site conservation amongst 15 laboratory mouse strains. Genome Biol. 2012;13:26.
20. Bazak L, Haviv A, Barak M, Jacob-Hirsch J, Deng P, Zhang R, et al. A-to-I RNA editing occurs at over a hundred million genomic sites, located in a majority of human genes. Genome Res. 2014;24:365-76.
21. O'Connell MA, Keller W. Purification and properties of double-stranded RNA-specific adenosine deaminase from calf thymus. Cell Biol. 1994;91:105-10600.
22. Smith HC, Bennett RP, Kizilyer A, McDougall WM, Prohaska KM. Functions and regulation of the APOBEC family of proteins. Semin Cell Dev Biol. 2012;23:258-68.
23. Blanc V, Davidson NO. APOBEC-1-mediated RNA editing. Wiley Interdiscip Rev Syst Biol Med. 2010;2:594-602.
24. Powell LM, Wallis SC, Pease RJ, Edwards YH, Knott TJ, Scott J. A novel form of tissue-specific RNA processing produces apolipoprotein-B48 in intestine. Cell. 1987;50:831-40.
25. Chen S, Habib G, Yang C, Gu Z, Lee B, Weng S, et al. Apolipoprotein B-48 is the product of a messenger RNA with an organ-specific in-frame stop codon. Science. 1987;238:363-6.
26. Sharma S, Patnaik SK, Taggart RT, Kannisto ED, Enriquez SM, Gollnick P, et al. APOBEC3A cytidine deaminase induces RNA editing in monocytes and macrophages. Nat Commun. 2015;6:6881.
27. Blanc V, Park E, Schaefer S, Miller M, Lin Y, Kennedy S, et al. Genome-wide identification and functional analysis of Apobec-1-mediated C-to-U RNA editing in mouse small intestine and liver. Genome Biol. 2014;15:R79.
28. Rosenberg BR, Hamilton CE, Mwangi MM, Dewell S, Papavasiliou FN. Transcriptome-wide sequencing reveals numerous APOBEC1 mRNA-editing targets in transcript 3 UTRs. Nat Struct Mol Biol. 2011;18:230-6.
29. Kyewski B, Derbinski J. Self-representation in the thymus: an extended view. Nat Rev Immunol. 2004;4:688-98.
30. Anderson AC, Nicholson LB, Legge KL, Turchin V, Zaghouani H, Kuchroo VK. High frequency of autoreactive myelin proteolipid protein-specific T cells in the periphery of naive mice: mechanisms of selection of the self-reactive repertoire. J Exp Med. 2000;191:761-70.
31. Kyewski B, Klein L. A central role for central tolerance. Annu Rev Immunol. 2006;24:571-606.
32. Merkin J, Russell C, Chen P, Burge CB. Evolutionary dynamics of gene and isoform regulation in Mammalian tissues. Science. 2012;338:1593-9.
33. St-Pierre C, Brochu S, Vanegas JR, Dumont-Lagacé M, Lemieux S, Perreault C. Transcriptome sequencing of neonatal thymic epithelial cells. Sci Rep. 2013;3:1860.
34. Soumillon M, Necsulea A, Weier M, Brawand D, Zhang X, Gu H, et al. Cellular source and mechanisms of high transcriptome complexity in the mammalian testis. Cell Rep. 2013;3:2179-90.
35. Ramsköld D, Wang ET, Burge CB, Sandberg R. An abundance of ubiquitously expressed genes revealed by tissue transcriptome sequence data. PLoS Comput Biol. 2009;5:e1000598.
36. Johnson MB, Kawasawa YI, Mason CE, Krsnik Z, Coppola G, Bogdanović D, et al. Functional and evolutionary insights into human brain development through global transcriptome analysis. Neuron. 2009;62:494-509.
37. Schmidt EE. Transcriptional promiscuity in testes. Curr Biol. 1996;6:768-9.
38. Sansom SN, Shikama-Dorn N, Zhanybekova S, Nusspaumer G, Macaulay IC, Deadman ME, et al. Population and single-cell genomics reveal the Aire dependency, relief from Polycomb silencing, and distribution of self-antigen expression in thymic epithelia. Genome Res. 2014;24:1918-31.
39. Meredith M, Zemmour D, Mathis D, Benoist C. Aire controls gene expression in the thymic epithelium with ordered stochasticity. Nat Immunol. 2015;16:942-9.
40. Brennecke P, Reyes A, Pinto S, Rattay K, Nguyen M, Küchler R, et al. Single-cell transcriptome analysis reveals coordinated ectopic gene-expression patterns in medullary thymic epithelial cells. Nat Immunol. 2015;16:933-41.
41. Kyewski B, Derbinski J, Gotter J, Klein L. Promiscuous gene expression and central T-cell tolerance: more than meets the eye. Trends Immunol. 2002;23:364-71.
42. Keane P, Ceredig R, Seoighe C. Promiscuous mRNA splicing under the control of AIRE in medullary thymic epithelial cells. Bioinformatics. 2015;31:986-90.
43. Grabowski PJ, Black DL. Alternative RNA splicing in the nervous system. Prog Neurobiol. 2001;65:289-308.
44. Shen S, Park JW, Lu Z, Lin L, Henry MD, Wu YN, et al. rMATS: Robust and flexible detection of differential alternative splicing from replicate RNA-Seq data. Proc Natl Acad Sci. 2014;111:E5593-601.
45. Cooke MP, Perlmutter RM. Expression of a novel form of the fyn proto-oncogene in hematopoietic cells. New Biol. 1989;1:66-74.
46. Karolchik D, Baertsch R, Diekhans M, Furey TS, Hinrichs A, Lu YT, et al. The UCSC Genome Browser Database. Nucleic Acids Res. 2003;31:51-4.
47. Farajollahi S, Maas S. Molecular diversity through RNA editing: a balancing act. Trends Genet. 2010;26:221-30.
48. Conticello SG. The AID/APOBEC family of nucleic acid mutators. Genome Biol. 2008;9:229.
49. Paul MS, Bass BL. Inosine exists in mRNA at tissue-specific levels and is most abundant in brain mRNA. EMBO J. 1998;17:1120-7.
50. Young SG. Recent progress in understanding apolipoprotein B. Circulation. 1990;82:1574-94.
51. Higuchi K, Kitagawa K, Kogishi K, Takeda T. Developmental and age-related changes in apolipoprotein B mRNA editing in mice. J Lipid Res. 1992;33:1753-64.
52. Anderson G, Takahama Y. Thymic epithelial cells: working class heroes for T cell development and repertoire selection. Trends Immunol. 2012;33:256-63.
53. Stritesky GL, Jameson SC, Hogquist KA. Selection of self-reactive T cells in the thymus. Annu Rev Immunol. 2012;30:95-114.
54. Aschenbrenner K, D'Cruz LM, Vollmann EH, Hinterberger M, Emmerich J, Swee LK, et al. Selection of Foxp3+ regulatory T cells specific for self antigen expressed and presented by Aire + medullary thymic epithelial cells. Nat Immunol. 2007;8:351-8.
55. Cowan JE, Parnell SM, Nakamura K, Caamano JH, Lane PJL, Jenkinson EJ, et al. The thymic medulla is required for Foxp3+ regulatory but not conventional CD4+ thymocyte development. J Exp Med. 2013;210:675-81.
56. Wang ET, Cody NAL, Jog S, Biancolella M, Wang TT, Treacy DJ, et al. Transcriptome-wide regulation of pre-mRNA splicing and mRNA localization by muscleblind proteins. Cell. 2012;150:710-24.
57. Metzger TC, Khan IS, Gardner JM, Mouchess ML, Johannes KP, Krawisz AK, et al. Lineage tracing and cell ablation identify a post-Aire-expressing thymic epithelial cell population. Cell Rep. 2013;5:166-79.
58. Lkhagvasuren E, Sakata M, Ohigashi I, Takahama Y. Lymphotoxin β receptor regulates the development of CCL21-expressing subset of postnatal medullary thymic epithelial cells. J Immunol. 2013;190:5110-7.
59. Derbinski J, Gäbler J, Brors B, Tierling S, Jonnakuty S, Hergenhahn M, et al. Promiscuous gene expression in thymic epithelial cells is regulated at multiple levels. J Exp Med. 2005;202:33-45.
60. Amor S, Groome N, Linington C, Morris MM, Dornmair K, Gardinier MV, et al. Identification of epitopes of myelin oligodendrocyte glycoprotein for the induction of experimental allergic encephalomyelitis in SJL and Biozzi AB/H mice. J Immunol. 1994;153:4349-56.
61. Sakamoto Y, Matsumoto T, Mizunoe Y, Haraoka M, Sakumoto M, Kumazawa J. Testicular injury induces cell-mediated autoimmune response to testis. J Urol. 1995;153:1316-20.
62. Ritchie W, Granjeaud S, Puthier D, Gautheret D. Entropy measures quantify global splicing disorders in cancer. PLoS Comput Biol. 2008;4:e1000011.
63. Pickrell JK, Pai AA, Gilad Y, Pritchard JK. Noisy splicing drives mRNA isoform diversity in human cells. PLoS Genet. 2010;6:e1001236.
64. Melamud E, Moult J. Stochastic noise in splicing machinery. Nucleic Acids Res. 2009;37:4873-86.
65. Chuprin A, Avin A, Goldfarb Y, Herzig Y, Levi B, Jacob A, et al. The deacetylase Sirt1 is an essential regulator of Aire-mediated induction of central immunological tolerance. Nat Immunol. 2015;16:737-45.
66. Dobin A, Davis CA, Schlesinger F, Drenkow J, Zaleski C, Jha S, et al. STAR: ultrafast universal RNA-seq aligner. Bioinformatics. 2013;29:15-21.
67. Liao Y, Smyth GK, Shi W. featureCounts: an efficient general purpose program for assigning sequence reads to genomic features. Bioinformatics. 2013;30:923-30.
68. Li B, Dewey CN. RSEM: accurate transcript quantification from RNA-Seq data with or without a reference genome. BMC Bioinformatics. 2011;12:323.
69. Picardi E, Pesole G. REDItools: high-throughput RNA editing detection made easy. Bioinformatics. 2013;29:1813-4.
70. Wang K, Li M, Hakonarson H. ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data. Nucleic Acids Res. 2010;38:e164.
71. Anders S, Huber W. DESeq: Differential expression analysis for sequence count data. Genome Biol. 2010;11:R106.
72. Fiume M, Williams V, Brook A, Brudno M. Savant: genome browser for high-throughput sequencing data. Bioinformatics. 2010;26:1938-44.