Group leader, Research Director (DR2)
Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Strasbourg, France Inserm, France
UCSC genome browser screenshots showing the ChIP-Seq binding profiles of Smc1 and Smc3 at the IgH locus (chr12:114,438,857-114,669,149) in resting and activated (with LPS + IL-4) B cells isolated from wild-type mice. A schematic map of the IgH locus indicates the switch regions (black boxes), the constant region exons (white boxes), the E enhancer and the DNAseI hypersensitive sites (hs) located in the 3′ regulatory region (3′RR).
The cohesin complex (Smc1 and Smc3) is dynamically recruited to the IgH locus in B cells undergoing immunoglobulin class switch recombination © 2014
Bernardo Reina San Martin is interested in the molecular mechanisms driving the diversification of the repertoire of B-cells, the cells of our immune system producing antibodies. He specifically investigates somatic hypermutation (SHM) and class switch recombination (CSR), two processes involved in the immune response to generate an antibody mediated answer, which is long lasting and highly specific.
During the immune response, the generation of highly specific and adapted humoral responses is achieved by mechanisms initiated by DNA damage inflicted by Activation-induced cytidine deaminase (AID), an enzyme that deaminates cytosines to uracils in DNA. These lesions are processed to introduce mutations in immunoglobulin (Ig) variable regions during somatic hypermutation (SHM) or to generate double stranded DNA break intermediates in Ig switch regions during class switch recombination (CSR). While on-target DNA lesions are crucial for triggering antibody diversification, off-target lesions and/or aberrant DNA repair can initiate malignancy. Although DNA deamination by AID has been clearly established as the mechanism that initiates antibody diversification, the questions of how AID selects its genomic targets and how AID-induced DNA damage is accurately repaired, remain largely unanswered.
The core activity of Bernardo Reina-San-Martin’s lab is directed towards elucidation of the molecular mechanisms driving antibody diversification, with a specific focus on the protein complexes involved in mediating AID targeting and in repairing AID-induced DNA damage in vivo.
The projects currently developed in Bernardo Reina-San-Martin’s laboratory aim at increasing our knowledge about the molecular mechanisms driving the diversification of the B cell repertoire during immune responses through somatic hypermutation (SHM) and class switch recombination (CSR). In addition, they would like to further understand the mechanisms that enforce genome stability and integrity in response to programmed DNA damage induced by AID.
Some of the specific questions that they address are:
1/ How is the function of AID function regulated in vivo ?
2/ What are the proteins that associate with AID and what is their functional role in CSR and SHM ?
3/ By which mechanism is the access of AID to chromatin controlled ?
4/ What is the role of transcription in the genome-wide recruitment of AID ?
5/ How is AID-induced DNA damage efficiently repaired ?
6/ How is the outcome of AID recruitment differentially regulated between immunoglobulin (Ig) and non-Ig loci ?
7/ What are the protein complexes involved in repairing AID-induced DNA damage?
The approaches they use to address these questions include: molecular and cellular techniques, gene targeting/transgenesis in mice, shRNA-mediated knockdown, in vitro cell differentiation assays, protein identification by mass spectrometry, flow cytometry, chromatin immunoprecipitation (ChIP), ChIP-Seq analysis, and more recently CRISPR/Cas9 genome editing.
• 2000 Ph. D. in Immunology, Pasteur Institute, Paris, France, Paola Minoprio's Lab, Evolution of the B cell repertoire during an infectious challenge with Trypanosoma cruzi
• 2000-2006 Post-doctoral fellow, The Rockfeller University, HHMI, New York, USA, Michel Nussenzweig's lab, Function of activation induced cytidine deaminase (AID) in B cell receptor diversification
• 2006 Appoint Group leader at the IGBMC, Strasbourg, France
• 2007 Appointed Inserm Scientist (CR1), Inserm, France
• 2010 Appointed Research Director (DR2), Inserm, France
• 2015 Laureate Association Alsace Contre le Cancer
• Elected member at The Henry Kunkel Society, USA, 2010
• Scientific Prize, Comité Alsace de la Fondation pour la Recherche Médicale (FRM), 2009
• AVENIR starting grant, Inserm, 2007
• Mexican’s National AIDS Research Award, Fondation pour la Recherche Médicale (FRM), 1995
May 2015, PLoS Genet.
Nov 2013, J Exp Med
Jan 2011, Molecular Cell