The IgH Eµ-MAR regions promote UNG-dependent error-prone repair to optimize somatic hypermutation

International audienceIntroduction: Two scaffold/matrix attachment regions (5'-and 3'-MARs Eμ) flank the intronic core enhancer (cEμ) within the immunoglobulin heavy chain locus (IgH). Besides their conservation in mice and humans, the physiological role of MARs Eμ is still unclear and their involvement in somatic hypermutation (SHM) has never been deeply evaluated.Methods: Our study analyzed SHM and its transcriptional control in a mouse model devoid of MARs Eμ , further combined to relevant models deficient for base excision repair and mismatch repair. Results: We observed an inverted substitution pattern in of MARs Eμ-deficient animals: SHM being decreased upstream from cEμ and increased downstream of it. Strikingly, the SHM defect induced by MARs Eμ-deletion was accompanied by an increase of sense transcription of the IgH V region, excluding a direct transcription-coupled effect. Interestingly, by breeding to DNA repair-deficient backgrounds, we showed that the SHM defect, observed upstream from cEμ in this model, was not due to a decrease in AID deamination but rather the consequence of a defect in base excision repair-associated unfaithful repair process.Discussion: Our study pointed out an unexpected "fence" function of MARs Eμ regions in limiting the error-prone repair machinery to the variable region of Ig gene loci