E. Afgan, D. Baker, M. Beek, . Van-den, D. Blankenberg et al., The Galaxy platform for accessible , reproducible and collaborative biomedical analyses : 2016 update, Nucleic Acids Research, vol.44, pp.3-10, 2016.
URL : https://hal.archives-ouvertes.fr/hal-01360125

N. Aluru, E. Kuo, L. W. Helfrich, S. I. Karchner, A. Elwood et al., Developmental exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin alters DNA methyltransferase (dnmt) expression in zebrafish (Danio rerio), Toxicol Appl Pharmacol, vol.284, issue.2, pp.142-151, 2016.

A. Ansar, The immune system as a potential target for environmental estrogens (endocrine disrupters): a new emerging field, Toxicology, vol.150, pp.191-206, 2000.

A. Bansal, J. Henao-mejia, and R. A. Simmons, Immune System: An Emerging Player in Mediating Effects of Endocrine Disruptors on Metabolic Health, Endocrinology, pp.32-45, 2017.

B. Bo?i? and B. Rozman, Apoptosis and Autoimmunity, Clinical Immunology, vol.17, issue.3, pp.69-74, 2006.

H. Chuang, C. Tsai, C. Hsueh, and T. Tan, GLK-IKK signaling induces dimerization and translocation of the AhR-RORt complex in IL-17A induction and autoimmune disease, Science Advances, pp.1-16, 2018.

T. Colborn, F. S. Vom-saal, and A. M. Soto, Developmental effects of endocrinedisrupting chemicals in wildlife and humans, vol.101, pp.378-384, 1993.

K. H. Costenbader, S. Gay, M. E. Alarcón-riquelme, L. Iaccarino, and A. Doria, , 2012.

, epigenetic regulation and environmental factors : Which is the most relevant in developing autoimmune diseases ?, Autoimmunity Reviews, vol.11, issue.8, pp.604-609

M. A. Cron, S. Maillard, F. Delisle, N. Samson, F. Truffault et al., Analysis of microRNA expression in the thymus of Myasthenia Gravis patients opens new research avenues, Autoimmunity Reviews, vol.17, issue.6, pp.588-600, 2018.
URL : https://hal.archives-ouvertes.fr/hal-01844365

P. Cufi, N. Dragin, N. Ruhlmann, J. M. Weiss, E. Fadel et al., Central role of interferon-beta in thymic events leading to myasthenia gravis, Journal of Autoimmunity, vol.52, pp.44-52, 2014.
URL : https://hal.archives-ouvertes.fr/hal-01514459

N. M. Danzl, S. Jeong, Y. Choi, and K. Alexandropoulos, Identification of Novel Thymic Epithelial Cell Subsets Whose Differentiation Is Regulated by RANKL and Traf6, PLoS One, vol.9, issue.1, 2014.

J. Derbinski and B. Kyewski, How thymic antigen presenting cells sample the body's self-antigens, Current Opinion in Immunology, vol.22, issue.5, pp.592-600, 2010.

,

J. Derbinski, S. Pinto, S. Ro, K. Hexel, and B. Kyewski, Promiscuous gene expression patterns in single medullary thymic epithelial cells argue for a stochastic mechanism, Proceedings of the National Academy of Sciences, vol.105, pp.657-662, 2008.

J. Dooley, M. Erickson, and A. G. Farr, Alterations of the medullary epithelial compartment in the Aire-deficient thymus: Implications for programs of thymic epithelial differentiation, J Immunol, vol.181, issue.8, pp.5225-5232, 2008.

!. ,

N. Dragin, J. Bismuth, G. Cizeron-clairac, M. G. Biferi, C. Berthault et al., Estrogen-mediated downregulation of AIRE influences sexual dimorphism in autoimmune diseases, The Journal of Clinical Investigation, vol.126, issue.4, pp.1525-1537, 2016.
URL : https://hal.archives-ouvertes.fr/hal-01310502

D. Garcia-domingo, D. Ramirez, G. Gonzalez-de-buitrago, and C. Martinez-a, Death Inducer-Obliterator 1 Triggers Apoptosis after Nuclear Translocation and Caspase Upregulation, Molecular and Cellular Biology, vol.23, issue.9, pp.3216-3225, 2003.

,

A. Gradolatto, D. Nazzal, M. Foti, J. Bismuth, F. Truffault et al., Defects of immunoregulatory mechanisms in myasthenia gravis: Role of IL-17, Annals of the New York Academy of Sciences, vol.1274, issue.1, pp.40-47, 2012.

A. Gradolatto, D. Nazzal, F. Truffault, J. Bismuth, E. Fadel et al., Both Treg cells and Tconv cells are defective in the Myasthenia gravis thymus: Roles of IL-17 and TNF-?, Journal of Autoimmunity, vol.52, pp.53-63, 2014.

O. Idowu, K. T. Semple, K. Ramadass, W. O'connor, P. Hansbro et al., Beyond the obvious: Environmental health implications of polar polycyclic aromatic hydrocarbons, Environment International, vol.123, pp.543-557, 2019.

F. Jühling, H. Kretzmer, S. H. Bernhart, C. Otto, P. F. Stadler et al., metilene : fast and sensitive calling of differentially methylated regions from bisulfite sequencing data, Genome Research, vol.26, pp.256-262, 2016.

,

R. E. Kabir, S. M. Rahman, and I. Rahman, A review on endocrine disruptors and their possible impacts on human health, Environmental Toxicology and Pharmacology, vol.40, issue.1, pp.241-258, 2015.

F. Krueger, Trim Galore! Available at, 2015.

R. Le-panse, J. Bismuth, and S. Berrih-aknin, Microarrays Reveal Distinct Gene Signatures in the Thymus of Seropositive and Seronegative Myasthenia Gravis Patients and the Role of CC Chemokine Ligand 21 in Thymic, The Journal of Immunology, vol.177, issue.11, pp.7868-7879, 2006.

A. Lerner, P. Jeremias, and T. Matthias, The World Incidence and Prevalence of Autoimmune Diseases is Increasing, International Journal of Celiac Disease, vol.3, issue.4, pp.151-155, 2015.

J. Matthews and J. Gustafsson, Estrogen receptor and aryl hydrocarbon receptor signaling pathways, Nuclear Receptor Signaling, 2006.

B. S. Pedersen, K. Eyring, S. De, I. V. Yang, and D. A. Schwartz, Fast and accurate alignment of long bisulfite-seq reads, ArXiv.Org, pp.1-2, 2014.

S. Poradosu, B. Bravenboer, R. Takatani, and H. Jüppner, Pseudohypoparathyroidism type 1B caused by methylation changes at the GNAS complex locus, BMJ Case Rep, pp.1-3, 2016.

T. Rao and B. Richardson, Environmentally Induced Autoimmune Diseases : Potential Mechanisms Modification of Cellular Gene, Perspect, vol.107, pp.737-742, 1999.

H. Reyes, S. Reisz-porszasz, and O. Hankinson, Identification of the Ah Receptor Nuclear Translocator Protein (Arnt) as a Component of the DNA Binding Form of the Ah Receptor, Science, vol.256, issue.5060, pp.1193-1195, 1992.

. !-!-#,

V. Rothhammer and F. J. Quintana, The aryl hydrocarbon receptor : an environmental sensor integrating immune responses in health and disease, Nature Reviews Immunology, p.19, 2019.

C. Selmi, Q. Lu, and M. C. Humble, Heritability versus the role of the environment in autoimmunity, Journal of Autoimmunity, vol.39, issue.4, pp.249-252, 2012.

,

J. Shen, W. Yu, M. Brotto, J. A. Scherman, C. Guo et al., Deficiency of MIP phosphatase induces a muscle disorder by disrupting Ca2+ homeostasis, Nat Cell Biol, vol.377, issue.2, pp.364-377, 2009.

,

N. P. Singh, U. P. Singh, B. Singh, R. L. Price, M. Nagarkatti et al., Activation of Aryl Hydrocarbon Receptor (AhR) Leads to Reciprocal Epigenetic Regulation of FoxP3 and IL-17 Expression and Amelioration of Experimental Colitis, PLoS One, issue.8, p.6, 2011.

V. Vasilev, A. F. Daly, A. Thiry, P. Petrossians, F. Fina et al., McCune-Albright Syndrome : A Detailed Pathological and Genetic Analysis of Disease Effects in an Adult Patient, J Clin Endocrinol Metab, vol.99, pp.2029-2038, 2014.
URL : https://hal.archives-ouvertes.fr/hal-01054166

M. Veldhoen, K. Hirota, A. M. Westendorf, J. Buer, L. Dumoutier et al., The aryl hydrocarbon receptor links T H 17-cell-mediated autoimmunity to environmental toxins, Nature, vol.453, pp.2-6, 2008.

,

J. A. Villegas, A. C. Bayer, K. Ider, J. Bismuth, F. Truffault et al., Il-23/Th17 cell pathway: A promising target to alleviate thymic inflammation maintenance in myasthenia gravis, Journal of Autoimmunity, vol.98, pp.59-73, 2018.
URL : https://hal.archives-ouvertes.fr/hal-02357775

C. Wang, X. Yuan, C. Liu, S. Zhai, D. Zhang et al., Preliminary research on DNA methylation changes during murine palatogenesis induced by TCDD, J Craniomaxillofac Surg, vol.45, issue.5, pp.678-684, 2017.

M. A. Wheeler, V. Rothhammer, and F. J. Quintana, Control of immune-mediated pathology via the aryl hydrocarbon receptor, J. Biol. Chem, vol.292, pp.12383-12389, 2017.

Q. Wu, S. Ohsako, R. Ishimura, J. S. Suzuki, and C. Tohyama, Exposure of Mouse Preimplantation Embryos to 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) Alters the Methylation Status of Imprinted Genes H19 and Igf2, Biology Of Reproduction, vol.70, pp.1790-1797, 2003.

I. Yevshin, R. Sharipov, T. Valeev, A. Kel, and F. Kolpakov, GTRD : a database of transcription factor binding sites identified by ChIP-seq experiments, Nucleic Acids Research, vol.45, pp.61-67, 2016.

, Diplôme : Ingénieur Agronome/Master 2 Spécialité : Biologie Moléculaire et Cellulaire (BMC)

, Biochimie (G2B) Enseignant référent : Lecerf Frédéric Auteur(s) : Ducreux Bastien Date de naissance, Spécialisation / option : Génétique, Génomique, pp.6-06

, Organisme d'accueil : Centre de Recherche en Myologie, p.974

, Adresse : 105, p.75013

P. Maître-de-stage, Dragin Nadine Nb, p.21

. Annexe, , p.0

A. De-soutenance, , 2019.

, Titre français : Impact de l'activation de AhR sur les processus moléculaires au niveau des cellules épithéliales thymiques

, En se fixant sur l'ADN ou en induisant des modifications épigénétiques, il régule l'expression de gènes cibles de l'auto-immunité et déséquilibre la balance des populations lymphocytaires Th17 et Treg. Dans cette étude, nous avons comparé les profils d'expression de gènes cibles de AhR dérégulés dans la myasthénie auto-immune avec ceux de cellules thymiques exposées à différents ligands de AhR et y avons retrouvé des similarités. Dans un second temps, après avoir montré une surexpression des méthyltransférases suite à une exposition aux ligands de AhR et dans les cellules de patients myasthéniques, nous avons identifié à l'échelle du génome des régions promotrices communes différentiellement méthylées. Deux ont été identifiées dans KRT5 et GNAS, gènes en lien avec l'auto-immunité. ! Abstract : Autoimmune diseases are a group of 80 pathologies arising from dysfunctional immune central tolerance mechanism. Their feminine prevalence as well as their high incidence in industrialized countries have raised questions and concerns about environmental exposure to xenoestrogens, described as endocrine disruptors, which could play a leading role in the development of autoimmune pathologies. Toxicity of these chemicals is mediated through Aryl Hydrocarbon Receptor (AhR), Titre anglais : Impact of AhR activation on molecular processes in thymic epithelial cells Résumé : Les maladies auto-immunes sont un groupe de 80 pathologies ayant pour origine un dysfonctionnement du mécanisme de tolérance immune centrale. Leur prévalence féminine et leur incidence dans les pays industrialisés ont récemment soulevé la question de l'influence des xénoestrogènes, décrits comme perturbateurs endocriniens, dans le développement de ces maladies

, Mots-clés : Aryl Hydrocarbon Receptor, autoimmunité, méthylation de l'ADN, myasthenia gravis, perturbateurs endocriniens