IntroductionThe immunoglobulin heavy chain locus (IgH) undergoes multiple changes along B-cell differentiation, affecting transcription and accessibility to V(D)J or class switch recombination (CSR). The iE enhancer upstream of C mostly promotes V(D)J recombination, 1 whereas IgH 3ЈRR enhancers (hs3a, hs1,2, hs3b, and hs4) have controversial roles. A role in CSR was suggested by replacing mouse hs1,2 with a neomycin resistance gene, thus affecting germline transcription and CSR to ␥2a, ␥2b, ␥3, and ⑀. 2 However, deletion of this neo cassette restored CSR. 3 hs3a, hs3b, and hs4 also proved individually dispensable for CSR. 3-5 Enhancer redundancies might explain that their individual deletion only results in minor effect. Indeed, joint hs3b/hs4 deletion impaired germline transcription and CSR to most isotypes except and ␥1. 6 Reporter genes also demonstrated synergies between 3ЈRR enhancers, 7 which altogether promote CSR into large transgenes. 8 The 3ЈRR is followed with DNase hypersensitive sites (hs5-7) lacking enhancer activity but binding CCCTC-binding factor and constituting the 3Ј locus boundary. 9 To reconcile the controversial phenotypes of focal mutations, potentially attenuated by functional redundancies, we evaluated IgH expression and CSR after deleting the whole 30-kb extent of the 3ЈRR.

Somatic hypermutation in variable heavy chain rearranged regions is abrogated in the absence of the 3′ regulatory region enhancer, whereas transcription rate in the Ig heavy chain is only partially reduced.

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