Epigenetic aspects of lymphocyte antigen receptor gene rearrangement or ‘when stochasticity completes randomness’

Authors

  • Sébastien Jaeger,

    1. Centre d'Immunologie de Marseille-Luminy (CIML), Institut National de la Santé et de la Recherche Médicale (Inserm) U1104, Centre National de la Recherche Scientifique (CNRS)UMR7280, Aix-Marseille University UM2, Marseille, France
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  • Bastien Fernandez,

    1. Centre de Physique Théorique, CNRS, UMR 7332, Aix-Marseille University, Université de Toulon, Campus de Luminy, Marseille, France
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  • Pierre Ferrier

    Corresponding author
    • Centre d'Immunologie de Marseille-Luminy (CIML), Institut National de la Santé et de la Recherche Médicale (Inserm) U1104, Centre National de la Recherche Scientifique (CNRS)UMR7280, Aix-Marseille University UM2, Marseille, France
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Correspondence: Pierre Ferrier, Centre d'Immunologie de Marseille-Luminy, Parc Scientifique et Technologique de Luminy, Case 906, 13288 Marseille Cedex 09, France. Email: ferrier@ciml.univ-mrs.fr

Senior author: Pierre Ferrier

Summary

To perform their specific functional role, B and T lymphocytes, cells of the adaptive immune system of jawed vertebrates, need to express one (and, preferably, only one) form of antigen receptor, i.e. the immunoglobulin or T-cell receptor (TCR), respectively. This end goal depends initially on a series of DNA cis-rearrangement events between randomly chosen units from separate clusters of V, D (at some immunoglobulin and TCR loci) and J gene segments, a biomolecular process collectively referred to as V(D)J recombination. V(D)J recombination takes place in immature T and B cells and relies on the so-called RAG nuclease, a site-specific DNA cleavage apparatus that corresponds to the lymphoid-specific moiety of the VDJ recombinase. At the genome level, this recombinase's mission presents substantial biochemical challenges. These relate to the huge distance between (some of) the gene segments that it eventually rearranges and the need to achieve cell-lineage-restricted and developmentally ordered routines with at times, mono-allelic versus bi-allelic discrimination. The entire process must be completed without any recombination errors, instigators of chromosome instability, translocation and, potentially, tumorigenesis. As expected, such a precisely choreographed and yet potentially risky process demands sophisticated controls; epigenetics demonstrates what is possible when calling upon its many facets. In this vignette, we will recall the evidence that almost from the start appeared to link the two topics, V(D)J recombination and epigenetics, before reviewing the latest advances in our knowledge of this joint venture.

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