The IgH locus 3′ cis-regulatory super-enhancer co-opts AID for allelic transvection

// Sandrine Le Noir 1,* , Brice Laffleur 1,* , Claire Carrion 1 , Armand Garot 1 , Sandrine Lecardeur 1 , Eric Pinaud 1 , Yves Denizot 1 , Jane Skok 2 and Michel Cogne 1 1 UMR 7276 CNRS and Universite de Limoges: Controle de la Reponse Immune B et Lymphoproliferation, Limoges, France 2 Department of Pathology, New York University School of Medicine, New York, NY, USA * These authors have contributed equally to this work Correspondence to: Michel Cogne, email: // Keywords : super-enhancer; alleles; transvection; nuclear positioning; gene regulation Received : December 20, 2016 Accepted : January 01, 2017 Published : Janaury 10, 2017 Abstract Immunoglobulin heavy chain ( IgH ) alleles have ambivalent relationships: they feature both allelic exclusion, ensuring monoallelic expression of a single immunoglobulin (Ig) allele, and frequent inter-allelic class-switch recombination (CSR) reassembling genes from both alleles. The IgH locus 3’ regulatory region (3’RR) includes several transcriptional cis -enhancers promoting activation-induced cytidine deaminase (AID)-dependent somatic hypermutation (SHM) and CSR, and altogether behaves as a strong super-enhancer. It can also promote deregulated expression of translocated oncogenes during lymphomagenesis. Besides these rare, illegitimate and pathogenic interactions, we now show that under physiological conditions, the 3’RR super-enhancer supports not only legitimate cis- , but also trans- recruitment of AID, contributing to IgH inter-allelic proximity and enabling the super-enhancer on one allele to stimulate biallelic SHM and CSR. Such inter-allelic activating interactions define transvection, a phenomenon well-known in drosophila but rarely observed in mammalian cells, now appearing as a unique feature of the IgH 3’RR super-enhancer.