Stepwise activation of the immunoglobulin mu 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 his tone acetylation, occurs in discrete, independently regulated domains. Init ially, a 120 kb domain of germline DNA is hyperacetylated, that extends fro m D-FL16.1, the 5'-most D-H gene segment, to the intergenic region between C mu and C delta. Germline V-H genes were not hyperacetylated at this stage , which accounts for D-H to J(H) recombination occurring first during B-cel l development. Subsequent activation of the V-H locus happens in at least t hree differentially regulated domains: an interleukin-7-regulated domain co nsisting of the 5' J558 family, an intermediate domain and the 3' V-H genes , which are hyperacetylated in response to DJ(H) recombination. These obser vations lead to mechanisms for two well-documented phenomena in B-cell onto geny: the sequential rearrangement of D-H followed by V-H gene segments, an d 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 lar ge segments of the genome are prepared for expression.