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,,|| The Children's Hospital, Boston, Massachusetts 02115; and the Center for Blood Research and || Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115
The 40-kb region downstream of the most 3' immunoglobulin (Ig) heavy chain constant region gene (C
) contains a series of transcriptional enhancers speculated to play a role in Ig heavy chain class switch recombination (CSR). To elucidate the function of this putative CSR regulatory region, we generated mice with germline mutations in which one or the other of the two most 5' enhancers in this cluster (respectively referred to as HS3a and HS1,2) were replaced either with a pgk-neor cassette (referred to as HS3aN and HS1,2N mutations) or with a loxP sequence (referred to as HS3a
and HS1,2, respectively). B cells homozygous for the HS3aN or HS1,2N mutations had severe defects in CSR to several isotypes. The phenotypic similarity of the two insertion mutations, both of which were cis-acting, suggested that inhibition might result from pgk-neor cassette gene insertion rather than enhancer deletion. Accordingly, CSR returned to normal in B cells homozygous for the HS3a or HS1,2 mutations. In addition, induced expression of the specifically targeted pgk-neor genes was regulated similarly to that of germline CH genes. Our findings implicate a 3' CSR regulatory locus that appears remarkably similar in organization and function to the β-globin gene 5' LCR and which we propose may regulate differential CSR via a promoter competition mechanism.
Key Words: immunoglobulin genes • class switching • enhancers • gene-targeted mutation • transcription
The first three authors contributed equally to this work.
Abbreviations used: CSR, class switch recombination; ES, embryonic stem; H, Ig heavy; LCR, locus control region.
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