Group Leader
The aim of the team is to understand the molecular mechanisms that control, in vivo, the interactions between regulatory elements at the immunoglobulin heavy chain locus, and the transcriptional and epigenetic mechanisms involved in the recruitment of the enzymes that mediate antibody diversification processes and associated chromosomal translocations.
The major goal of our team is to decipher the molecular mechanisms underlying antibody diversification and their deregulation in B-cell cancers.
By using a combination of genetic, functional and mechanistic analyses, we investigate the molecular mechanisms that control antibody diversification. We focus on two processes, namely V(D)J recombination and class switch recombination (CSR), and on the pathological consequences of their deregulation.
Developing B lymphocytes have a remarkable capacity to somatically alter their genome through V(D)J recombination. This process is catalyzed by the RAG1/2 complex which introduces DNA double-strand breaks at specific signal sequences within the variable regions of their immunoglobulin (Ig) loci.
Mature B cells have the unique ability to undergo an additional recombination process, CSR, initiated by the enzyme AID (Activation-Induced cytidine Deaminase), which targets highly repetitive sequences within the constant genes of the Ig heavy chain (IgH) locus.
Both V(D)J recombination and CSR are controlled by distant regulatory elements on the chromosome. These include promoters, enhancers and insulators, which engage in long-range interactions in a developmental stage-specific manner.
Our aim is to understand the transcriptional and epigenetic mechanisms that control these interactions in vivo and how the cross-talk between IgH regulatory elements activates or silences IgH locus expression.
In some ill-understood circumstances, the RAG1/2 complex and AID can target non-Ig loci potentially leading to genomic instability and cancer.
Our objective is to understand the role of these enzymes in B-cell cancers, with a special focus on B-cell acute lymphoblastic leukemia.
A. Amine Khamlichi (CNRS)
Dylan Andrieux
Audrey Dauba (University)
Kawtar Hanefioui
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
Jamrog*, Chemin* et al. (2018) PAX5-ELN oncoprotein promotes multistep B-cell acute lymphoblastic leukemia in mice. Proc Natl Acad Sci USA
Braikia et al. (2017) Inducible CTCF insulator delays the IgH 3′ regulatory region-mediated activation of germline promoters and alters class switching. Proc Natl Acad Sci USA
We are grateful to our past and present national and international collaborators:
Prizes
June 2021 – Dr Chloé Oudinet is awarded the Toulouse Academy of sciences prize for her PhD work.
Press Releases
The complete list of our publications is available through Pubmed.
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
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
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 :