Aire controls gene expression in the thymic epithelium with ordered stochasticity

Nature Immunology

Volumn 16, Issue 9, 2015, Pages 942-949

  Meredith, Matthew ^a   Zemmour, David ^a   Mathis, Diane ^a   Benoist, Christophe ^a  

^a BRIGHAM AND WOMEN S HOSPITAL   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

AUTOIMMUNE REGULATOR PROTEIN; GREEN FLUORESCENT PROTEIN; TRANSCRIPTOME; MESSENGER RNA; TRANSCRIPTION FACTOR;

ALTERNATIVE RNA SPLICING; ANIMAL CELL; ARTICLE; BACTERIAL ARTIFICIAL CHROMOSOME; DNA METHYLATION; EPITHELIUM; EXON; FALSE NEGATIVE RESULT; FLOW CYTOMETRY; GENE CLUSTER; GENE EXPRESSION; MOUSE; NONHUMAN; PRIORITY JOURNAL; PROMOTER REGION; RNA SEQUENCE; SINGLE CELL ANALYSIS; STATISTICS; THYMIC EPITHELIUM; THYMOCYTE; TRANSCRIPTION INITIATION; ANIMAL; CYTOLOGY; EPITHELIUM CELL; GENE EXPRESSION REGULATION; GENETICS; IMMUNOLOGICAL TOLERANCE; IMMUNOLOGY; METABOLISM; THYMUS;

ANIMALS; DNA METHYLATION; EPITHELIAL CELLS; GENE EXPRESSION REGULATION; MICE; RNA, MESSENGER; SELF TOLERANCE; SINGLE-CELL ANALYSIS; THYMUS GLAND; TRANSCRIPTION FACTORS;

EID: 84939622896     PISSN: 15292908     EISSN: 15292916     Source Type: Journal    
DOI: 10.1038/ni.3247     Document Type: Article

References (50)

1. Peterson, P., Org, T., Rebane, A. Transcriptional regulation by AIRE: molecular mechanisms of central tolerance. Nat. Rev. Immunol. 8, 948-957 (2008).
2. Anderson, M.S. et al. Projection of an immunological self shadow within the thymus by the aire protein. Science 298, 1395-1401 (2002).
3. Hubert, F.X. et al. Aire regulates the transfer of antigen from mTECs to dendritic cells for induction of thymic tolerance. Blood 118, 2462-2472 (2011).
4. Liston, A. et al. Aire regulates negative selection of organ-specific T cells. Nat. Immunol. 4, 350-354 (2003).
5. Anderson, M.S. et al. The cellular mechanism of Aire control of T cell tolerance. Immunity 23, 227-239 (2005).
6. Malchow, S. et al. Aire-dependent thymic development of tumor-associated regulatory T cells. Science 339, 1219-1224 (2013).
7. Waterfield, M. et al. The transcriptional regulator Aire coopts the repressive ATF7ip-MBD1 complex for the induction of immunotolerance. Nat. Immunol. 15, 258-265 (2014).
8. Org, T. et al. The autoimmune regulator PHD finger binds to non-methylated histone H3K4 to activate gene expression. EMBO Rep. 9, 370-376 (2008).
9. Koh, A.S. et al. Aire employs a histone-binding module to mediate immunological tolerance, linking chromatin regulation with organ-specific autoimmunity. Proc. Natl. Acad. Sci. USA 105, 15878-15883 (2008).
10. Giraud, M. et al. Aire unleashes stalled RNA polymerase to induce ectopic gene expression in thymic epithelial cells. Proc. Natl. Acad. Sci. USA 109, 535-540 (2012).
11. Abramson, J., Giraud, M., Benoist, C., Mathis, D. Aire's partners in the molecular control of immunological tolerance. Cell 140, 123-135 (2010).
12. Gaetani, M. et al. AIRE-PHD fingers are structural hubs to maintain the integrity of chromatin-associated interactome. Nucleic Acids Res. 40, 11756-11768 (2012).
13. Oven, I. et al. AIRE recruits P-TEFb for transcriptional elongation of target genes in medullary thymic epithelial cells. Mol. Cell. Biol. 27, 8815-8823 (2007).
14. Giraud, M. et al. An RNAi screen for Aire cofactors reveals a role for Hnrnpl in polymerase release and Aire-activated ectopic transcription. Proc. Natl. Acad. Sci. USA 111, 1491-1496 (2014).
15. Villasenõr, J., Besse, W., Benoist, C., Mathis, D. Ectopic expression of peripheral-tissue antigens in the thymic epithelium: probabilistic, monoallelic, misinitiated. Proc. Natl. Acad. Sci. USA 105, 15854-15859 (2008).
16. Taubert, R., Schwendemann, J., Kyewski, B. Highly variable expression of tissue-restricted self-antigens in human thymus: implications for self-tolerance and autoimmunity. Eur. J. Immunol. 37, 838-848 (2007).
17. Derbinski, J. et al. Promiscuous gene expression patterns in single medullary thymic epithelial cells argue for a stochastic mechanism. Proc. Natl. Acad. Sci. USA 105, 657-662 (2008).
18. Pinto, S. et al. Overlapping gene coexpression patterns in human medullary thymic epithelial cells generate self-antigen diversity. Proc. Natl. Acad. Sci. USA 110, E3497-E3505 (2013).
19. Venanzi, E.S., Melamed, R., Mathis, D., Benoist, C. The variable immunological self: genetic variation and nongenetic noise in Aire-regulated transcription. Proc. Natl. Acad. Sci. USA 105, 15860-15865 (2008).
20. Shapiro, E., Biezuner, T., Linnarsson, S. Single-cell sequencing-based technologies will revolutionize whole-organism science. Nat. Rev. Genet. 14, 618-630 (2013).
21. Elowitz, M.B., Levine, A.J., Siggia, E.D., Swain, P.S. Stochastic gene expression in a single cell. Science 297, 1183-1186 (2002).
22. Ozbudak, E.M. et al. Regulation of noise in the expression of a single gene. Nat. Genet. 31, 69-73 (2002).
23. Kalmar, T. et al. Regulated fluctuations in nanog expression mediate cell fate decisions in embryonic stem cells. PLoS Biol. 7, e1000149 (2009).
24. Shalek, A.K. et al. Single-cell RNA-seq reveals dynamic paracrine control of cellular variation. Nature 510, 363-369 (2014).
25. Trapnell, C. et al. The dynamics and regulators of cell fate decisions are revealed by pseudotemporal ordering of single cells. Nat. Biotechnol. 32, 381-386 (2014).
26. Ross, I.L., Browne, C.M., Hume, D.A. Transcription of individual genes in eukaryotic cells occurs randomly and infrequently. Immunol. Cell Biol. 72, 177-185 (1994).
27. Wu, A.R. et al. Quantitative assessment of single-cell RNA-sequencing methods. Nat. Methods 11, 41-46 (2014).
28. Kharchenko, P.V., Silberstein, L., Scadden, D.T. Bayesian approach to single-cell differential expression analysis. Nat. Methods 11, 740-742 (2014).
29. Gardner, J.M. et al. Deletional tolerance mediated by extrathymic Aire-expressing cells. Science 321, 843-847 (2008).
30. Sansom, S.N. 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. 24, 1918-1931 (2014).
31. Klein, L. et al. Shaping of the autoreactive T-cell repertoire by a splice variant of self protein expressed in thymic epithelial cells. Nat. Med. 6, 56-61 (2000).
32. Anderson, A.C. et al. 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. 191, 761-770 (2000).
33. Keane, P., Ceredig, R., Seoighe, C. Promiscuous mRNA splicing under the control of AIRE in medullary thymic epithelial cells. Bioinformatics 31, 986-990 (2015).
34. Hashimshony, T., Wagner, F., Sher, N., Yanai, I. CEL-Seq: single-cell RNA-Seq by multiplexed linear amplification. Cell Rep. 2, 666-673 (2012).
35. Islam, S. et al. Quantitative single-cell RNA-seq with unique molecular identifiers. Nat. Methods 11, 163-166 (2014).
36. Bodenhofer, U., Kothmeier, A., Hochreiter, S. APCluster: an R package for affinity propagation clustering. Bioinformatics 27, 2463-2464 (2011).
37. Johnnidis, J.B. et al. Chromosomal clustering of genes controlled by the aire transcription factor. Proc. Natl. Acad. Sci. USA 102, 7233-7238 (2005).
38. Derbinski, J. et al. Promiscuous gene expression in thymic epithelial cells is regulated at multiple levels. J. Exp. Med. 202, 33-45 (2005).
39. Su, A.I. et al. Large-scale analysis of the human and mouse transcriptomes. Proc. Natl. Acad. Sci. USA 99, 4465-4470 (2002).
40. van der Maaten, L., Hinton, G. Visualizing high-dimensional data using t-SNE. J. Mach. Learn. Res. 9, 2579-2605 (2008).
41. Gu, H. et al. Preparation of reduced representation bisulfite sequencing libraries for genome-scale DNA methylation profiling. Nat. Protoc. 6, 468-481 (2011).
42. Ball, M.P. et al. Targeted and genome-scale strategies reveal gene-body methylation signatures in human cells. Nat. Biotechnol. 27, 361-368 (2009).
43. Org, T. et al. AIRE activated tissue specific genes have histone modifications associated with inactive chromatin. Hum. Mol. Genet. 18, 4699-4710 (2009).
44. Raser, J.M., O'Shea, E.K. Control of stochasticity in eukaryotic gene expression. Science 304, 1811-1814 (2004).
45. Tao, Y. et al. AIRE recruits multiple transcriptional components to specific genomic regions through tethering to nuclear matrix. Mol. Immunol. 43, 335-345 (2006).
46. Gill, J., Malin, M., Hollander, G.A., Boyd, R. Generation of a complete thymic microenvironment by MTS24+ thymic epithelial cells. Nat. Immunol. 3, 635-642 (2002).
47. Zhao, R. et al. Gene bookmarking accelerates the kinetics of post-mitotic transcriptional re-activation. Nat. Cell Biol. 13, 1295-1304 (2011).
48. Le Borgne, M. et al. The impact of negative selection on thymocyte migration in the medulla. Nat. Immunol. 10, 823-830 (2009).
49. Merkenschlager, M., Benoist, C., Mathis, D. Evidence for a single-niche model of positive selection. Proc. Natl. Acad. Sci. USA 91, 11694-11698 (1994).
50. Krueger, F., Andrews, S.R. Bismark: a flexible aligner and methylation caller for Bisulfite-Seq applications. Bioinformatics 27, 1571-1572 (2011).