AID targeting is dependent on RNA polymerase II pausing

Abstract

Activation induced deaminase (AID) is globally targeted to immunoglobulin loci, preferentially focused to switch (S) regions and variable (V) regions, and prone to attack hotspot motifs. Nevertheless, AID deamination is not exclusive to Ig loci and the rules regulating AID targeting remain unclear. Transcription is critically required for class switch recombination and somatic hypermutation. Here, I consider the unique features associated with S region transcription leading to RNA polymerase II pausing, that in turn promote the introduction of activating chromatin remodeling, histone modifications and recruitment of AID to targeted S regions. These findings allow for a better understanding of the interplay between transcription, AID targeting and mistargeting to Ig and non-Ig loci.

Fig. 1

AID creates DSBs in a looped Igh locus. The diagram (not to scale) shows VDJ exons (blue box), the intronic µ enhancer, Eµ (yellow circle), Sµ, Sγ3, Sγ1 and Sγ2b regions (orange, red, green and blue ovals, respectively), I exons (black rectangles), C_H genes (gray boxes) and the 3′Eα regulatory regions (gray filled circle). (A) Following B cell activation with LPS and IL4 both the µ and γ1 GLTs are expressed. (B) In resting B cells the Igh locus is in a looped configuration tethered by long range interactions between Eµ and 3′Eα. (C) Upon treatment with LPS and IL4 the γ1 GLT promoter interacts with 3′Eα and brings Sγ1 into proximity with Sµ (D) B cell activation also activates AID that in turn generates DSBs in Sµ and Sγ1. The DSBs are resolved by a reciprocal recombination event which generates an excision circle and a new hybrid Sµ/Sγ1 junction along the chromosome, thereby facilitating IgG1 expression.