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Immunoglobulin heavy chain gene regulation through polyadenylation and splicing competition

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Abstract 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. WIREs RNA 2011 2 92–105 DOI: 10.1002/wrna.36 This article is categorized under: RNA Processing > Splicing Regulation/Alternative Splicing RNA Processing > 3' End Processing RNA in Disease and Development > RNA in Development

The 3 end structure of immunoglobulin heavy chain genes. IgH genes contain common structural features involved in alternative RNA processing to produce two mRNAs from a single primary transcript. The solid boxes are exons that are common to the two mRNAs, the gray boxes are the portion of the mRNA that remains in the secretory‐specific mRNA, the open boxes are exons that are only found in membrane‐associated mRNA, diamonds identify the two poly(A) signals, the 5 and 3 splice sites that compete with the secretory poly(A) signal are labeled, angled lines above identify RNA splicing reactions. While the gene features are conserved among the IgH genes, the specific lengths of the elements vary. The size range of the various introns and exons that are found in the IgM, IgD, IgG, IgA, and IgE genes are shown below the map. The gray outlined open box indicates that not all IgH genes contain two membrane‐specific exons. The two mRNAs produced are shown below and the ratio of these two mRNAs in B cells and plasma cells is identified.

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Patterns of alternative RNA processing that were tested to explore IgH regulatory mechanisms. (a) RNA splicing and poly(A) signal competition as in the IgH genes and the DdpA genes.37,38 (b) Poly(A) signal competition without a competing RNA splice reaction.39–41 (c) Alternative 5 splice site choice without a competing poly(A) signal.42–44 (d) Alternative splicing or intron retention without a competing poly(A) signal.44.

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Features of the IgM gene that affect RNA processing patterns, but not the developmental regulation. (a) While searching for gene‐specific regulatory sequences, many parts of the IgM gene have been modified, as delineated by the brackets below the map. These features are described in the text and have been reported in Refs 23,24,26,27,29,31,32. The coding of the map is as described in Figure 1. (b) Multiple features contribute to the overall strength of the µsec poly(A) signal. The region between the Cµ4 5 splice site and downstream RNA pol II pause region is shown, including the spacing between the 5 splice site and the core AAUAAA sequence, the core sequence and the cleavage site (CA and downward arrow), the cleavage site and the proximal GU‐rich element, the cleavage site and the distal GU‐rich element and the distal GU‐rich element and the end of the deletion defining the pause site region. The gray bar indicates an upstream region that contains both positive and negative‐acting sequences identified by mutagenesis.33,34 The AU‐rich region surrounding the core AAUAAA,33,35 the two unusually located GU‐rich sequences32,33,35,36 and the pol II pause site region32 are shown.

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RNA in Disease and Development > RNA in Development
RNA Processing > Splicing Regulation/Alternative Splicing
RNA Processing > 3′ End Processing

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