ETS1 and PAX5 transcription factors recruit AID to Igh DNA

Abstract

B lymphocytes optimize antibody responses by class switch recombination (CSR), which changes the expressed constant region exon of the immunoglobulin heavy chain (IgH), and by somatic hypermutation (SH) that introduces point mutations in the variable regions of the antibody genes. Activation-induced cytidine deaminase (AID) is the key mutagenic enzyme that initiates both these antibody diversification processes by deaminating cytosine to uracil. Here we asked the question if transcription factors can mediate the specific targeting of the antibody diversification by recruiting AID. We have recently reported that AID is together with the transcription factors E2A, PAX5 and IRF4 in a complex on key sequences of the Igh locus. Here we report that also ETS1 is together with AID in this complex on key sequences of the Igh locus in splenic B cells of mice. Furthermore, we show that both ETS1 and PAX5 can directly recruit AID to DNA sequences from the Igh locus with the specific binding site for the transcription factor. Taken together, our findings support the notion of a targeting mechanism for the selective diversification of antibody genes with limited genome wide mutagenesis by recruitment of AID by PAX5 and ETS1 in a transcription factor complex.

Mutagenic Activity of AID/APOBEC Deaminases in Antiviral Defense and Carcinogenesis

“…The mechanisms providing AID selectivity for immunoglobulin genes are not fully understood. The transcription factors ETS1 and PAX5 have been shown to play a key role in the recruitment of AID to the immunoglobulin heavy chain sequences in mice; the proteins E2A and IRF4 are also involved in the formation of the complex [32]. In mice, ETS1 is expressed in many tissues during embryonic and early postnatal development; however, in adult mice and humans, the expression of this protein is observed mainly in the organs of the immune system: thymus, spleen, and lymph nodes.…”

Helix-Loop-Helix Proteins in Adaptive Immune Development

“…E2A proteins also bind directly to Ig genes to promote SHM and CSR. E2A forms a complex with AID, Pax5, ETS1 and IRF4 that functions to target AID to sites within the Igh locus ( 94 , 95 ). E2A and E2-2 promote CSR by opening chromatin at the 3’RR enhancer and activating GLT of switch regions.…”

Genome Instability in Multiple Myeloma: Facts and Factors

“…BLIMP1 and IRF4 bind to 3′RR and regulate transcription at IGH locus; BLIMP1 also represses transcription of AICDA and BCL6 , whereas IRF4 activates AICDA expression [ 200 , 217 , 605 ]. AID co-localizes with several transcription factors, including PAX5 and IRF4, at the IGH locus, which might play a role in AID targeting to specific locations [ 606 , 607 ]. Chromatin-remodeling factors ARID1A and CHD4 facilitate nucleosome reorganization required for transcription through S-regions.…”