Instabilité Génétique et Régulation Transcriptionnelle
Responsable d'équipe
Notre objectif est de comprendre les mécanismes transcriptionnels et épigénétiques qui contrôlent le locus des chaînes lourdes des anticorps au cours du développement des lymphocytes B, et le rôle du complexe RAG et AID dans la leucémie aigüe lymphoblastique B.
L’objectif majeur de l’équipe IGRT est d’élucider les mécanismes moléculaires sous-jacents à la diversité des anticorps et aux cancers B.
L’équipe explore les mécanismes moléculaires qui diversifient les anticorps et le rôle d’enzymes spécifiques dans la leucémie aigüe lymphoblastique B par une combinaison d’analyses génétiques, fonctionnelles et mécanistiques.
Les cellules B précoces ont la remarquable capacité de diversifier les loci des immunoglobulines (Ig) grâce à la recombinaison V(D)J, catalysée par le complexe RAG1/2. Les cellules B matures ont la capacité unique de diversifier leurs anticorps grâce à la commutation de classe, initiée par l’enzyme AID (Activation-Induced cytidine Deaminase), qui cible des séquences hautement répétitives de la région constante du locus des chaînes lourdes des Ig (IgH).
La recombinaison V(D)J et la commutation de classe sont contrôlées par des éléments de régulation distants sur le chromosome. Ces éléments, incluant promoteurs, enhancers et insulateurs, sont engagés dans des interactions de longue distance qui varient en fonction du stade de développement.
Notre objectif est de comprendre les mécanismes transcriptionnels et épigénétiques qui contrôlent ces interactions in vivo et comment ces interactions régulent l’expression du locus IgH au cours du développement B.
La leucémie aigüe lymphoblastique B (LAL-B) est le cancer pédiatrique le plus fréquent. Elle se caractérise par un blocage de la différenciation des lymphocytes B précoces combiné à une prolifération anarchique des cellules blastiques. Nous avons mis au point un nouveau modèle murin qui récapitule les étapes essentielles à la survenue de la LAL-B humaine.
En utilisant ce modèle, l’équipe a pour objectif d’élucider le rôle du complexe RAG et d’AID le déclenchement de la LAL-B.
Team members
Research Scientist
Ahmed Amine Khamlichi (CNRS)
Research Engineers
Audrey Dauba (University)
PhD student
Kawtar Hanefioui
Our research projects
Transcriptional and epigenetic regulation of antibody diversification
Molecular mechanisms underlying B-cell acute lymphoblastic leukemia
Oudinet et al. (2022) Switch Tandem Repeats Influence the Choice of the Alternative End-Joining Pathway in Immunoglobulin Class Switch Recombination. Front Immunol
Dauba et al. (2021) Interleukin 7 regulates switch transcription in developing B cells. Cell Mol Immunol
Oudinet et al. (2020) Recombination may occur in the absence of transcription in the immunoglobulin heavy chain recombination centre. Nucleic Acids Res
Santos et al. (2019) Two modes of cis-activation of switch transcription by the IgH superenhancer. Proc Natl Acad Sci USA
Oudinet et al (2019) Developmental regulation of DNA cytosine methylation at the immunoglobulin heavy chain constant locus. PLoS Genet
Jamrog*, Chemin* et al. (2018) PAX5-ELN oncoprotein promotes multistep B-cell acute lymphoblastic leukemia in mice. Proc Natl Acad Sci USA
Scheme of a rearranged mouse IgH locus with its major regulatory elements. V(D)J recombination, CSR and associated chromosomal translocations are mediated by the RAG complex and AID respectively.
Prizes
June 2021 – Dr Chloé Oudinet is awarded the Toulouse Academy of sciences prize for her PhD work.
Press Releases
- Transcription versus recombination in the generation of antibody diversity
- In some instances, more is better…for the IgH super-enhancer
- DNA methylation: Better mark the locus before it’s too late…
- Pour une expression précise des gènes des anticorps, un commutateur temporel est nécessaire…
The complete list of our publications is available through Pubmed.
2024
- Dauba, A., Näser, E., Andrieux, D., Cogné, M., Denizot, Y., Khamlichi, A.A. The immunoglobulin heavy chain super enhancer controls class switch recombination in developing B cells. (2024). Sci Rep 14, 7370.
- Fregona, V., Bayet, M., Bouttier, M., Largeaud, L., Hamelle, C., Jamrog, L.A., Prade, N., Lagarde, S., Hebrard, S., Luquet, I., Mansat-De Mas, V., Nolla, M., Pasquet, M., Didier, C., Khamlichi, A.A., Broccardo, C., Delabesse, É., Mancini, S.J.C., Gerby, B. (2024). Stem cell-like reprogramming is required for leukemia-initiating activity in B-ALL. J Exp Med 221, e20230279.
2023
- Denis-Lagache, N, Oblet, C, Marchiol, T, Baylet, A, Têteau, O, Dalloul, I, Dalloul, Z, Zawil, L, Dézé, O, Cook-Moreau, J, Saintamand, A, Boutouil, H, Khamlichi, AA, Carrion, C, Péron, S, Le Noir, S, Laffleur, B, Cogné, M. (2023). Attempts to evaluate locus suicide recombination and its potential role in B cell negative selection in the mouse. Front Immunol 14, 1155906.
2022
- Oudinet, C., Zhang, X., Puget, N., Kyritsis, N., Leduc, C., Braikia, F.Z., Dauba, A., Alt, F.W., Khamlichi, A.A. (2022) Switch Tandem Repeats Influence the Choice of the Alternative End-Joining Pathway in Immunoglobulin Class Switch Recombination. Front Immunol 13, 870933
2021
- Dauba, A., Braikia, F.Z., Oudinet, C., Khamlichi, A.A. (2021) Interleukin 7 regulates switch transcription in developing B cells. Cell Mol Immunol 18, 776-778
- Dauba, A., Khamlichi, A.A. (2021) Long-Range Control of Class Switch Recombination by Transcriptional Regulatory Elements. Front Immunol 12, 738216
2020
- Oudinet, C., Braikia, F.Z., Dauba, A., Khamlichi, A.A. (2020) Mechanism and regulation of class switch recombination by IgH transcriptional control elements. Adv Immunol 147, 89-137
Oudinet, C., Braikia, F.Z., Dauba, A., Khamlichi, A.A. (2020) Recombination may occur in the absence of transcription in the immunoglobulin heavy chain recombination centre. Nucleic Acids Res 48, 3553-3566
2019
Oudinet, C., Braikia, F.Z., Dauba, A., Santos, J.M., Khamlichi, A.A. (2019) Developmental regulation of DNA cytosine methylation at the immunoglobulin heavy chain constant locus. PLoS Genet 15, e1007930
2018
- Khamlichi, A.A., Feil, R. (2018) Parallels between Mammalian Mechanisms of Monoallelic Gene Expression.Trends Genet 34, 954-971
- Jamrog, L., Chemin, G., Fregona, V., Coster, L., Pasquet, M., Oudinet, C., Rouquie, N., Prade, N., Lagarde, S., Cresson, C., Hebrard, S., Nguyen Huu, N.S., Bousquet, M., Quelen, C., Brousset, P., Mancini, S.J.C., Delabesse, E., Khamlichi, A.A., Gerby, B., Broccardo, C. (2018) PAX5-ELN oncoprotein promotes multistep B-cell acute lymphoblastic leukemia in mice. Proc Natl Acad Sci USA 115, 10357-10362115(41):10357-10362
- Santos, J.M., Braikia, F.Z., Oudinet, C., Haddad, D., Conte, C., Dauba, A., Khamlichi, A.A. (2018) Duplication of a germline promoter downstream of the IgH 3′ regulatory region impairs class switch recombination. Sci Rep 8, 9164
2017
- Braikia, F.Z., Oudinet, C., Haddad, D., Oruc, Z., Orlando, D., Dauba, A., Le Bert, M., Khamlichi, A.A. (2017) Inducible CTCF insulator delays the IgH 3′ regulatory region-mediated activation of germline promoters and alters class switching. Proc Natl Acad Sci USA 114, 6092-6097
2015
- Braikia, F.Z., Conte, C., Moutahir, M., Denizot, Y., Cogne, M., Khamlichi, A.A. (2015) Developmental Switch in the Transcriptional Activity of a Long-Range Regulatory Element. Mol Cell Biol 35, 3370-3380
- Puget, N., Leduc, C., Oruc, Z., Moutahir, M., Le Bert, M., Khamlichi, A.A. (2015) Complete cis Exclusion upon Duplication of the Emu Enhancer at the Immunoglobulin Heavy Chain Locus. Mol Cell Biol 35, 2231-2241
- Puget, N., Hirasawa, R., Hu, N.S., Laviolette-Malirat, N., Feil, R., Khamlichi, A.A. (2015) Insertion of an imprinted insulator into the IgH locus reveals developmentally regulated, transcription-dependent control of V(D)J recombination. Mol Cell Biol 35, 529-543
2014
- Braikia, F.Z., Chemin, G., Moutahir, M., Khamlichi, A.A. (2014) Quantification of V(D)J recombination by real-time quantitative PCR. Immunol Lett 162, 119-123
- Leduc, C., Chemin, G., Puget, N., Sawan, C., Moutahir, M., Herceg, Z., Khamlichi, A.A. (2014) Tissue-specific inactivation of HAT cofactor TRRAP reveals its essential role in B cells. Cell Cycle 13, 1583-1589
2011
- Haddad, D., Puget, N., Laviolette-Malirat, N., Conte, C., Khamlichi, A.A. (2011) Seeking sense of antisense switch transcripts. Transcription 2, 183-188
- Haddad, D., Oruc, Z., Puget, N., Laviolette-Malirat, N., Philippe, M., Carrion, C., Le Bert, M., Khamlichi, A.A. (2011) Sense transcription through the S region is essential for immunoglobulin class switch recombination. EMBO J 30, 1608-1620
2010
- Leduc, C., Haddad, D., Laviolette-Malirat, N., Nguyen Huu, N.S., Khamlichi, A.A. (2010) Combined deficiency of MSH2 and Smu region abolishes class switch recombination. Eur J Immunol 40, 2925-2931
- Zhang, T., Franklin, A., Boboila, C., McQuay, A., Gallagher, M.P., Manis, J.P., Khamlichi, A.A., Alt, F.W. (2010) Downstream class switching leads to IgE antibody production by B lymphocytes lacking IgM switch regions.Proc Natl Acad Sci USA 107, 3040-3045
- Haddad, D., Dougier, H.L., Laviolette, N., Puget, N., Khamlichi, A.A. (2010) Replacement of Imu-Cmu intron by NeoR gene alters Imu germ-line expression but has no effect on V(D)J recombination. Mol Immunol 47, 961-971
2009
- Rajagopal, D., Maul, R.W., Ghosh, A., Chakraborty, T., Khamlichi, A.A., Sen, R., Gearhart, P.J. (2009) Immunoglobulin switch mu sequence causes RNA polymerase II accumulation and reduces dA hypermutation. J Exp Med 206, 1237-1244
- Wang, L., Wuerffel, R., Feldman, S., Khamlichi, A.A., Kenter, A.L. (2009) S region sequence, RNA polymerase II, and histone modifications create chromatin accessibility during class switch recombination. J Exp Med 206, 1817-1830
2007
- Oruc, Z., Boumediene, A., Le Bert, M., Khamlichi, A.A. (2007) Replacement of Igamma3 germ-line promoter by Igamma1 inhibits class-switch recombination to IgG3. Proc Natl Acad Sci USA 104, 20484-20489
- Tessier, J., Cuvillier, A., Glaudet, F., Khamlichi, A.A. (2007) Internalization and molecular interactions of human CD21 receptor. Mol Immunol 44, 2415-2425
- Huang, F.T., Yu, K., Balter, B.B., Selsing, E., Oruc, Z., Khamlichi, A.A., Hsieh, C.L., Lieber, M.R. (2007) Sequence dependence of chromosomal R-loops at the immunoglobulin heavy-chain Smu class switch region. Mol Cell Biol 27, 5921-5932
2006
Samara, M., Oruc, Z., Dougier, H.L., Essawi, T., Cogne, M., Khamlichi, A.A. (2006) Germ line transcription in mice bearing neor gene downstream of Igamma3 exon in the Ig heavy chain locus. Int Immunol 18, 581-589
We are indebted to former PhD students and post-doctoral fellows who are now continuing their career in the best labs, enterprises and institutions :
- Fatima-Zohra Braikia, post-doctoral fellow at the NIH / NIA, Baltimore, USA
- Guillaume Chemin, Assistant professor, Limoges University, France
- Dania Haddad, Research Assistant. Dasman Diabetes Institute, Kuwait City, Kuwait
- Claire Leduc, Marketing department. Syntivia, Toulouse, France
- Chloé Oudinet, Research Engineer, Evotec, Toulouse, France
- Joana M Santos, Group leader, CNRS, I2BC, Gif-sur-Yvette, France