Localization of the 3 ' IgH locus elements that effect long-distance regulation of class switch recombination

Four transcriptional enhancers lie downstream of the immunoglobulin heavy c hain locus: C alpha3'/hs3a, hs1,2, hs3b, and hs4. Although individually wea k, these elements have strong transcriptional synergies when combined and t hey altogether behave as a locus control region. Previous knockout experime nts in the 3' region have shown that both hs3a and hs1,2 are dispensable fo r normal expression and rearrangement of the IgH locus but that their repla cement with a transcribed neo gene severely affects class switch recombinat ion. Here we show that even in the absence of a neo gene, joint deletion of the last two 3' enhancers, hs3b and hs4, severely impairs germline transcr iption and class switching to most isotypes and may in addition affect mu g ene expression in resting B cells.