Chd4 choreographs self-antigen expression for central immune tolerance.
Journal
Nature immunology
ISSN: 1529-2916
Titre abrégé: Nat Immunol
Pays: United States
ID NLM: 100941354
Informations de publication
Date de publication:
08 2020
08 2020
Historique:
received:
12
06
2019
accepted:
19
05
2020
pubmed:
1
7
2020
medline:
5
11
2020
entrez:
1
7
2020
Statut:
ppublish
Résumé
Autoreactive T cells are eliminated in the thymus to prevent autoimmunity by promiscuous expression of tissue-restricted self-antigens in medullary thymic epithelial cells. This expression is dependent on the transcription factor Fezf2, as well as the transcriptional regulator Aire, but the entire picture of the transcriptional program has been obscure. Here, we found that the chromatin remodeler Chd4, also called Mi-2β, plays a key role in the self-antigen expression in medullary thymic epithelial cells. To maximize the diversity of self-antigen expression, Fezf2 and Aire utilized completely distinct transcriptional mechanisms, both of which were under the control of Chd4. Chd4 organized the promoter regions of Fezf2-dependent genes, while contributing to the Aire-mediated induction of self-antigens via super-enhancers. Mice deficient in Chd4 specifically in thymic epithelial cells exhibited autoimmune phenotypes, including T cell infiltration. Thus, Chd4 plays a critical role in integrating Fezf2- and Aire-mediated gene induction to establish central immune tolerance.
Identifiants
pubmed: 32601470
doi: 10.1038/s41590-020-0717-2
pii: 10.1038/s41590-020-0717-2
doi:
Substances chimiques
Autoantigens
0
CHD4 protein, human
0
Transcription Factors
0
Mi-2 Nucleosome Remodeling and Deacetylase Complex
EC 3.5.1.98
Mi-2beta protein, mouse
EC 3.6.1.3
DNA Helicases
EC 3.6.4.-
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
892-901Subventions
Organisme : NIGMS NIH HHS
ID : R01 GM034277
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA133404
Pays : United States
Organisme : NCI NIH HHS
ID : P01 CA042063
Pays : United States
Références
Zinkernagel, R. M. & Doherty, P. C. Restriction of in vitro T cell-mediated cytotoxicity in lymphocytic choriomeningitis within a syngeneic or semiallogeneic system. Nature 248, 701–702 (1974).
pubmed: 4133807
Hogquist, K. A., Baldwin, T. A. & Jameson, S. C. Central tolerance: learning self-control in the thymus. Nat. Rev. Immunol. 5, 772–782 (2005).
pubmed: 16200080
pmcid: 16200080
Davis, M. M. et al. Ligand recognition by αβ T cell receptors. Annu Rev. Immunol. 16, 523–544 (1998).
pubmed: 9597140
Cheng, M. & Anderson, M. S. Thymic tolerance as a key brake on autoimmunity. Nat. Immunol. 19, 659–664 (2018).
pubmed: 29925986
pmcid: 6370479
Goodnow, C. C., Sprent, J., Fazekas de St Groth, B. & Vinuesa, C. G. Cellular and genetic mechanisms of self tolerance and autoimmunity. Nature 435, 590–597 (2005).
pubmed: 15931211
Klein, L., Kyewski, B., Allen, P. M. & Hogquist, K. A. Positive and negative selection of the T cell repertoire: what thymocytes see (and don’t see). Nat. Rev. Immunol. 14, 377–391 (2014).
pubmed: 24830344
pmcid: 4757912
Aschenbrenner, K. et al. Selection of Foxp3
pubmed: 17322887
Derbinski, J., Schulte, A., Kyewski, B. & Klein, L. Promiscuous gene expression in medullary thymic epithelial cells mirrors the peripheral self. Nat. Immunol. 2, 1032–1039 (2001).
pubmed: 11600886
Liston, A., Lesage, S., Wilson, J., Peltonen, L. & Goodnow, C. C. Aire regulates negative selection of organ-specific T cells. Nat. Immunol. 4, 350–354 (2003).
pubmed: 12612579
Rattay, K., Meyer, H. V., Herrmann, C., Brors, B. & Kyewski, B. Evolutionary conserved gene co-expression drives generation of self-antigen diversity in medullary thymic epithelial cells. J. Autoimmun. 67, 65–75 (2016).
pubmed: 26481130
The Finnish–German APECED Consortium. An autoimmune disease, APECED, caused by mutations in a novel gene featuring two PHD-type zinc-finger domains. Nat. Genet. 17, 399–403 (1997).
Nagamine, K. et al. Positional cloning of the APECED gene. Nat. Genet. 17, 393–398 (1997).
pubmed: 9398839
Giraud, M. et al. An IRF8-binding promoter variant and AIRE control CHRNA1 promiscuous expression in thymus. Nature 448, 934–937 (2007).
pubmed: 17687331
Colobran, R. et al. Association of an SNP with intrathymic transcription of TSHR and Graves’ disease: a role for defective thymic tolerance. Hum. Mol. Genet. 20, 3415–3423 (2011).
pubmed: 21642385
Gimenez-Barcons, M. et al. Autoimmune predisposition in Down syndrome may result from a partial central tolerance failure due to insufficient intrathymic expression of AIRE and peripheral antigens. J. Immunol. 193, 3872–3879 (2014).
pubmed: 25217160
Anderson, M. S. et al. Projection of an immunological self shadow within the thymus by the Aire protein. Science 298, 1395–1401 (2002).
Mathis, D. & Benoist, C. Aire. Annu Rev. Immunol. 27, 287–312 (2009).
pubmed: 19302042
Takaba, H. et al. Fezf2 orchestrates a thymic program of self-antigen expression for immune tolerance. Cell 163, 975–987 (2015).
pubmed: 26544942
Schug, J. et al. Promoter features related to tissue specificity as measured by Shannon entropy. Genome Biol. 6, R33 (2005).
pubmed: 15833120
pmcid: 1088961
Hassan, R. & Ho, M. Mesothelin targeted cancer immunotherapy. Eur. J. Cancer 44, 46–53 (2008).
pubmed: 17945478
Michaelidou, K., Tzovaras, A., Missitzis, I., Ardavanis, A. & Scorilas, A. The expression of the CEACAM19 gene, a novel member of the CEA family, is associated with breast cancer progression. Int. J. Oncol. 42, 1770–1777 (2013).
pubmed: 23525470
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).
pubmed: 25224068
pmcid: 4248310
Brennecke, P. et al. Single-cell transcriptome analysis reveals coordinated ectopic gene-expression patterns in medullary thymic epithelial cells. Nat. Immunol. 16, 933–941 (2015).
pubmed: 26237553
pmcid: 4675844
Meredith, M., Zemmour, D., Mathis, D. & Benoist, C. Aire controls gene expression in the thymic epithelium with ordered stochasticity. Nat. Immunol. 16, 942–949 (2015).
pubmed: 26237550
pmcid: 4632529
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).
pubmed: 24434558
Abramson, J., Giraud, M., Benoist, C. & Mathis, D. Aire’s partners in the molecular control of immunological tolerance. Cell 140, 123–135 (2010).
pubmed: 20085707
Tong, J. K., Hassig, C. A., Schnitzler, G. R., Kingston, R. E. & Schreiber, S. L. Chromatin deacetylation by an ATP-dependent nucleosome remodelling complex. Nature 395, 917–921 (1998).
pubmed: 9804427
Low, J. K. K. et al. CHD4 is a peripheral component of the nucleosome remodeling and deacetylase complex. J. Biol. Chem. 291, 15853–15866 (2016).
pubmed: 27235397
pmcid: 4957066
Stevens, T. J. et al. 3D structures of individual mammalian genomes studied by single-cell Hi-C. Nature 544, 59–64 (2017).
pubmed: 28289288
pmcid: 5385134
de Dieuleveult, M. et al. Genome-wide nucleosome specificity and function of chromatin remodellers in ES cells. Nature 530, 113–116 (2016).
pubmed: 26814966
pmcid: 4871117
Yoshida, T. et al. Chromatin restriction by the nucleosome remodeler Mi-2β and functional interplay with lineage-specific transcription regulators control B-cell differentiation. Genes Dev. 33, 763–781 (2019).
pubmed: 31123064
pmcid: 6601517
Zhang, J. et al. Harnessing of the nucleosome-remodeling-deacetylase complex controls lymphocyte development and prevents leukemogenesis. Nat. Immunol. 13, 86–94 (2011).
pubmed: 22080921
pmcid: 3868219
Hosokawa, H. et al. Functionally distinct Gata3/Chd4 complexes coordinately establish T helper 2 (Th2) cell identity. Proc. Natl Acad. Sci. USA 110, 4691–4696 (2013).
pubmed: 23471993
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).
pubmed: 24464130
pmcid: 4172453
Bansal, K., Yoshida, H., Benoist, C. & Mathis, D. The transcriptional regulator Aire binds to and activates super-enhancers. Nat. Immunol. 18, 263–273 (2017).
pubmed: 28135252
pmcid: 5310976
Hnisz, D. et al. Super-enhancers in the control of cell identity and disease. Cell 155, 934–947 (2013).
Yoshida, H. et al. Brd4 bridges the transcriptional regulators, Aire and P-TEFb, to promote elongation of peripheral-tissue antigen transcripts in thymic stromal cells. Proc. Natl Acad. Sci. USA 112, E4448–E4457 (2015).
pubmed: 26216992
Dowen, J. M. et al. Control of cell identity genes occurs in insulated neighborhoods in mammalian chromosomes. Cell 159, 374–387 (2014).
pubmed: 25303531
pmcid: 4197132
Lodato, S. et al. Gene co-regulation by Fezf2 selects neurotransmitter identity and connectivity of corticospinal neurons. Nat. Neurosci. 17, 1046–1054 (2014).
pubmed: 24997765
pmcid: 4188416
Seelig, H. P. et al. The major dermatomyositis-specific Mi-2 autoantigen is a presumed helicase involved in transcriptional activation. Arthritis Rheum. 38, 1389–1399 (1995).
pubmed: 7575689
Minnich, M. et al. Multifunctional role of the transcription factor Blimp-1 in coordinating plasma cell differentiation. Nat. Immunol. 17, 331–343 (2016).
pubmed: 26779602
pmcid: 5790184
Hoffmeister, H. et al. CHD3 and CHD4 form distinct NuRD complexes with different yet overlapping functionality. Nucleic Acids Res. 45, 10534–10554 (2017).
pubmed: 28977666
pmcid: 5737555
Torrado, M. et al. Refinement of the subunit interaction network within the nucleosome remodelling and deacetylase (NuRD) complex. FEBS J. 284, 4216–4232 (2017).
pubmed: 29063705
pmcid: 5734987
Suzuki, H. I., Young, R. A. & Sharp, P. A. Super-enhancer-mediated RNA processing revealed by integrative microRNA network analysis. Cell 168, 1000–1014.e15 (2017).
pubmed: 28283057
pmcid: 5350633
Lomada, D. et al. Stat3 signaling promotes survival and maintenance of medullary thymic epithelial cells. PLoS Genet. 12, e1005777 (2016).
pubmed: 26789196
pmcid: 4720390
Lewis, M. J. et al. Autoantibodies targeting TLR and SMAD pathways define new subgroups in systemic lupus erythematosus. J. Autoimmun. 91, 1–12 (2018).
pubmed: 29576246
Clement, C. C. et al. Autoimmune response to transthyretin in juvenile idiopathic arthritis. JCI Insight 1, 85633 (2016).
pubmed: 26973882
Tzartos, J. S. et al. Antibodies to aquaporins are frequent in patients with primary Sjögren’s syndrome. Rheumatology 56, 2114–2122 (2017).
pubmed: 28968830
Sjowall, C., Eriksson, P., Almer, S. & Skogh, T. Autoantibodies to C-reactive protein is a common finding in SLE, but not in primary Sjogren’s syndrome, rheumatoid arthritis or inflammatory bowel disease. J. Autoimmun. 19, 155–160 (2002).
pubmed: 12419286
Rapoport, B., Chazenbalk, G. D., Jaume, J. C. & McLachlan, S. M. The thyrotropin (TSH) receptor: interaction with TSH and autoantibodies. Endocr. Rev. 19, 673–716 (1998).
pubmed: 9861544
Han, W. et al. TBR1 directly represses Fezf2 to control the laminar origin and development of the corticospinal tract. Proc. Natl Acad. Sci. USA 108, 3041–3046 (2011).
pubmed: 21285371
O’Shaughnessy-Kirwan, A., Signolet, J., Costello, I., Gharbi, S. & Hendrich, B. Constraint of gene expression by the chromatin remodelling protein CHD4 facilitates lineage specification. Development 142, 2586–2597 (2015).
pubmed: 26116663
pmcid: 4529036
Kasai, M. et al. Difference in antigen presentation pathways between cortical and medullary thymic epithelial cells. Eur. J. Immunol. 26, 2101–2107 (1996).
pubmed: 8814253
Nitta, T. et al. The thymic cortical epithelium determines the TCR repertoire of IL-17-producing γδT cells. EMBO Rep. 16, 638–653 (2015).
pubmed: 25770130
pmcid: 4428049
Hayashi, M. et al. Osteoprotection by semaphorin 3A. Nature 485, 69–74 (2012).
pubmed: 22522930
Komatsu, N. et al. Pathogenic conversion of Foxp3
pubmed: 24362934
Langmead, B. & Salzberg, S. L. Fast gapped-read alignment with Bowtie 2. Nat. Methods 9, 357–359 (2012).
pubmed: 22388286
pmcid: 3322381
Langmead, B., Wilks, C., Antonescu, V. & Charles, R. Scaling read aligners to hundreds of threads on general-purpose processors. Bioinformatics 35, 421–432 (2018).
pmcid: 6361242
Shen, L., Shao, N., Liu, X. & Nestler, E. ngs.plot: Quick mining and visualization of next-generation sequencing data by integrating genomic databases. BMC Genomics 15, 284 (2014).
pubmed: 24735413
pmcid: 4028082
Ramírez, F. et al. deepTools2: a next generation web server for deep-sequencing data analysis. Nucleic Acids Res. 44, W160–W165 (2016).
pubmed: 27079975
pmcid: 4987876
Liao, Y., Smyth, G. K. & Shi, W. The Subread aligner: fast, accurate and scalable read mapping by seed-and-vote. Nucleic Acids Res. 41, e108 (2013).
pubmed: 23558742
pmcid: 3664803
Bodenhofer, U., Kothmeier, A. & Hochreiter, S. APCluster: an R package for affinity propagation clustering. Bioinformatics 27, 2463–2464 (2011).
pubmed: 21737437
Krzywinski, M. et al. Circos: an information aesthetic for comparative genomics. Genome Res. 19, 1639–1645 (2009).
pubmed: 2752132
pmcid: 2752132
Robinson, J. T. et al. Integrative genomics viewer. Nat. Biotechnol. 29, 24–26 (2011).
pubmed: 3346182
pmcid: 3346182
Zhang, Y. et al. Model-based analysis of ChIP-Seq (MACS). Genome Biol. 9, R137 (2008).
pubmed: 18798982
pmcid: 18798982
Heinz, S. et al. Simple combinations of lineage-determining transcription factors prime cis-regulatory elements required for macrophage and B cell identities. Mol. Cell 38, 576–589 (2010).
pubmed: 20513432
pmcid: 2898526
Žuklys, S. et al. Foxn1 regulates key target genes essential for T cell development in postnatal thymic epithelial cells. Nat. Immunol. 17, 1206–1215 (2016).
pubmed: 27548434
pmcid: 5033077
Lenda, D. M., Stanley, E. R. & Kelley, V. R. Negative role of colony-stimulating factor-1 in macrophage, T cell, and B cell mediated autoimmune disease in MRL-Fas
pubmed: 15383612
Koh, A. S. et al. Rapid chromatin repression by Aire provides precise control of immune tolerance. Nat. Immunol. 19, 162–172 (2018).
pubmed: 29335648
pmcid: 6049828
Akaike, H. Information Theory and an Extension of the Maximum Likelihood Principle (eds Petrov, B. N. & Caski, F.) 267–281 (Akadimiai Kiado, 1973).