Abstract
The Igκ locus undergoes a variety of different molecular processes during B cell development, including V(D)J rearrangement and somatic hypermutations (SHM), which are influenced by cis regulatory regions (RRs) within the locus. The Igκ locus includes three characterized RRs termed the intronic (iEκ), 3′Eκ, and Ed enhancers. We had previously noted that a region of DNA upstream of the iEκ and matrix attachment region (MAR) was necessary for demethylation of the locus in cell culture. In this study, we further characterized this region, which we have termed Dm, for demethylation element. Pre-rearranged Igκ transgenes containing a deletion of the entire Dm region, or of a Pax5-binding site within the region, fail to undergo efficient CpG demethylation in mature B cells in vivo. Furthermore, we generated mice with a deletion of the full Dm region at the endogenous Igκ locus. The most prominent phenotype of these mice is reduced SHM in germinal center B cells in Peyer’s patches. In conclusion, we propose the Dm element as a novel Pax5-binding cis regulatory element, which works in concert with the known enhancers, and plays a role in Igκ demethylation and SHM.
Highlights
The B cell receptors (BCRs) are encoded in the mouse genome by the three immunoglobulin (Ig) loci, the IgH heavy chain locus, and the two light chain loci, Igκ and Igλ
We find that, while the Dm element plays a role in demethylation of the Igκ locus in transgenes, this role is not translated to the endogenous locus, probably due to redundancy of the many enhancers of the locus, not all of which are present in the transgene
In this paper, we characterized a novel cis regulatory element situated within the Jκ–Cκ intron of the Igκ locus
Summary
The B cell receptors (BCRs) are encoded in the mouse genome by the three immunoglobulin (Ig) loci, the IgH heavy chain locus, and the two light chain loci, Igκ and Igλ. In their germline conformations, the Ig loci do not give rise to functional proteins. Each rearrangement utilizes a single V, D (in the heavy chain), and J segment, and each B cell contains one productively rearranged heavy chain and light chain. In this way, B cells give rise to the multitude of antigen recognition specificities which constitutes the adaptive immune system
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