Genetic Instability and Transcriptional Regulation

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.

Team members

Research Scientist

A. Amine Khamlichi (CNRS)

Research Engineers

Dylan Andrieux
Audrey Dauba (University)

PhD student

Kawtar Hanefioui

Our research projects

Transcriptional and epigenetic regulation of antibody diversification

Chromosomal translocations and B-cell cancers

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

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.