Stepwise activation of the immunoglobulin μ heavy chain gene locus

The immunoglobulin heavy chain (IgH) gene locus spans several megabases. We show that IgH activation during B-cell differentiation, as measured by histone acetylation, occurs in discrete, independently regulated domains. Initially, a 120 kb domain of germline DNA is hyperacetylated, that extends from D_FL16.1, the 5′-most D_H gene segment, to the intergenic region between Cμ and Cδ. Germline V_H genes were not hyperacetylated at this stage, which accounts for D_H to J_H, recombination occurring first during B-cell development. Subsequent activation of the V_H locus happens in at least three differentially regulated domains: an interleukin-7-regulated domain consisting of the 5′ J558 family, an intermediate domain and the 3′ V_H genes, which are hyperacetylated in response to DJ_H recombination. These observations lead to mechanisms for two well-documented phenomena in B-cell ontogeny: the sequential rearrangement of D_H followed by V_H gene segments, and the preferential recombination of D_H-proximal V_H genes in pro-B cells. We suggest that stepwise activation may be a general mechanism by which large segments of the genome are prepared for expression.