Immunoglobulin heavy chain gene regulation through polyadenylation and splicing competition

The immunoglobulin heavy chain (IgH) genes, which encode one of the two chains of antibody molecules, were the first cellular genes shown to undergo developmentally regulated alternative RNA processing. These genes produce two different mRNAs from a single primary transcript. One mRNA is cleaved and polyadenylated at an upstream poly(A) signal while the other mRNA removes this poly(A) signal by RNA splicing and is cleaved and polyadenylated at a downstream poly(A) site. A broad range of studies have been performed to understand the mechanism of IgH RNA processing regulation during B lymphocyte development. The model that has emerged is much more complex than envisioned by the earliest view of regulation through poly(A) signal choice. Regulation requires that the IgH gene contain competing splice and cleavage-polyadenylation reactions with balanced efficiencies. Because non-IgH genes with these structural features also can be regulated, IgH gene-specific sequence elements are not required for regulation. Changes in cleavage-polyadenylation and RNA splicing, as well as pol II elongation, all contribute to IgH developmental RNA processing regulation. Multiple factors are likely involved in the regulation during B lymphocyte maturation. Additional biologically relevant factors that contribute to IgH regulation remain to be identified and incorporated into a mechanistic model for regulation. Much of the work to date confirms the complex nature of IgH mRNA regulation and suggests that a thorough understanding of this control will remain a challenge. However, it is also likely that such understanding will help elucidate novel mechanisms of RNA processing regulation.