Estrogen receptors bind to and activate the promoter of the HoxC4 gene to potentiate HoxC4-mediated AID induction, immunoglobulin class-switch DNA recombination and somatic hypermutation (62.8)

Abstract

Abstract Estrogen enhances antibody and autoantibody responses through yet to be defined mechanisms. It has been suggested that estrogen upregulates the expression of activation-induced cytosine deaminase (AID), which is critical for antibody class switch DNA recombination (CSR) and somatic hypermutation (SHM), through direct activation of this gene. AID, as we have shown, is induced by the HoxC4 homeodomain transcription factor, which binds to a conserved HoxC4/Oct site in the AICDA/Aicda promoter. Here we show that estrogen-estrogen receptor (ER) complexes do not directly activate the AID promoter in B cells undergoing CSR. Rather, they bind to three evolutionary conserved and cooperative estrogen response elements (EREs) we identified in the HoxC4 gene promoter. By binding to these EREs, ERs synergized with CD154 or lipopolysaccharide (LPS) and IL-4-signaling to upregulate HoxC4 expression, thereby inducing AID and CSR, without affecting B cell proliferation or plasmacytoid differentiation. Estrogen administration in vivo significantly potentiated CSR and SHM in the specific antibody response to NP-CGG. Ablation of HoxC4 (HoxC4-/-) abrogated the estrogen-mediated enhancement of AID gene expression, and decreased CSR and SHM. Thus, estrogen enhances AID expression by activating the HoxC4 gene promoter and inducing the critical AID gene activator HoxC4.