A dynamic RNA hub facilitates activation induced cytidine deaminase recruitment to the immunoglobulin heavy chain locus

Abstract

Activation-induced cytidine deaminase (AID) converts cytosines to uracils within the actively transcribed switch regions to initiate DNA repair and formation of DNA double strand breaks required for immunoglobulin class switch recombination (CSR). How AID specifically targets switch regions remains a key unanswered question. Using a multimodal live cell single molecule imaging approach, we demonstrate that intronic switch regions promote robust transcription by enhancing polymerase loading and persistent transcriptional bursts, resulting in the formation of a dynamic RNA hub consisting of numerous nascent switch transcripts simultaneously tethered to the IgH locus. We further demonstrate that AID interacts with switch region RNA in vivo, and that this interaction is required for recruitment of AID to the IgH locus. Together, our findings show that the RNA hub formed by nascent switch region transcripts may be part of a "class switch recombination center" and drives the specific recruitment of AID to the IgH locus to initiate CSR.