METHYLATION STATUS OF IMMUNOGLOBULIN CHI GENE SEGMENTS CORRELATES WITH THEIR RECOMBINATION POTENTIAL

We have previously shown that unlike endogenous kappa genes, unrearranged kappa transgenes undergo Vkappa-Jkappa recombination in T as well as B cells of transgenic mice. To determine whether the difference in recombination specificity of the transgenic and endogenous kappa genes is associated with differences in DNA structure, the methylation status of the endogenous genes and three unrearranged kappa transgenes was compared. The Jkappa-Ckappa locus of the transgenes was found to be hypomethylated in all tissues of the transgenic mice. In contrast, methylation of the endogenous kappa genes was tissue and developmentally regulated. Hypomethylation of the endogenous Jkappa-Ckappa region occurs only in cells of the B lineage undergoing, or having completed kappa gene recombination. Transfection of fibroblasts from transgenic and control mice with the recombination activating genes, Rag1 and Rag2, led to a high level of rearrangement of the hypomethylated transgenic, but not the endogenous kappa genes. These results suggest that hypomethylation defines an accessible state of the kappa locus and that methylation/demethylation could be involved in the control of kappa gene rearrangement during lymphocyte differentiation.