Immunoglobulin gene transcription ceases upon deletion of a distant enhancer

The tissue-specific E mu enhancer within the immunoglobulin heavy chain (IgH) locus has recently been shown to be essential for efficient V region gene assembly in early B lineage cells. However, we and others have shown that late stage, Ig-secreting cells can produce IgH in the absence of E mu. In the present study we have explored the notion that another enhancer found in the far 3' region of the IgH locus (3' alpha E) takes on an important regulatory role in cells that have reached this terminal stage in B cell development. The technique of homologous recombination was used to disrupt the 3' alpha E region in an E mu-deficient, Ig gamma 2a-secreting cell line. Loss of 3' alpha E completely abolished Ig heavy chain gene expression, demonstrating that transcription of this gene was dependent upon sequences that reside over 70 kb downstream. The ability of these sequences to function efficiently in the absence of E mu may also provide an explanation for deregulated c-myc expression in many Ig-secreting tumors.