title: Estrogen receptors bind to and activate the HOXC4/HoxC4 promoter to potentiate HoxC4-mediated activation-induced cytosine deaminase induction, immunoglobulin class switch DNA recombination, and somatic hypermutation.
abstract: Estrogen enhances antibody and autoantibody responses through yet to be defined mechanisms. It has been suggested that estrogen up-regulates 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 gene promoter in B cells undergoing CSR. Rather, they bind to three evolutionarily conserved and cooperative estrogen response elements (EREs) we identified in the HOXC4/HoxC4 promoter. By binding to these EREs, ERs synergized with CD154 or LPS and IL-4 signaling to up-regulate 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 the 4-hydroxy-3-nitrophenylacetyl hapten conjugated with chicken γ-globulin. 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/HoxC4 promoter and inducing the critical AID gene activator, HoxC4.
authors.affiliation: Institute for Immunology, University of California, Irvine, California 92697-4120, USA.
authors.forename: Thach
authors.initials: T
authors.lastname: Mai
authors.forename: Hong
authors.initials: H
authors.lastname: Zan
authors.forename: Jinsong
authors.initials: J
authors.lastname: Zhang
authors.forename: J Seth
authors.initials: JS
authors.lastname: Hawkins
authors.forename: Zhenming
authors.initials: Z
authors.lastname: Xu
authors.forename: Paolo
authors.initials: P
authors.lastname: Casali
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology; D001483:Base Sequence; D002478:Cells, Cultured; D003564:Cytidine Deaminase / Q000235:genetics / Q000276:immunology*; D004789:Enzyme Activation; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D004967:Estrogens / Q000378:metabolism; D005260:Female; D018398:Homeodomain Proteins / Q000235:genetics* / Q000276:immunology; D006801:Humans; D017578:Immunoglobulin Class Switching; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D011995:Recombination, Genetic; D020218:Response Elements; D016415:Sequence Alignment; D027041:Somatic Hypermutation, Immunoglobulin; D015533:Transcriptional Activation; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
chemical_list: D047628:Estrogen Receptor alpha; D004967:Estrogens; C098691:HOXC4 protein, human; D018398:Homeodomain Proteins; C490904:Hoxc4 protein, mouse; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D003564:Cytidine Deaminase