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

J Biol Chem. 2010 Nov 26;285(48):37797-810. doi: 10.1074/jbc.M110.169086. Epub 2010 Sep 20.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • B-Lymphocytes / cytology
  • B-Lymphocytes / immunology
  • Base Sequence
  • Cells, Cultured
  • Cytidine Deaminase / genetics
  • Cytidine Deaminase / immunology*
  • Enzyme Activation
  • Estrogen Receptor alpha / genetics
  • Estrogen Receptor alpha / immunology*
  • Estrogen Receptor alpha / metabolism
  • Estrogens / metabolism
  • Female
  • Homeodomain Proteins / genetics*
  • Homeodomain Proteins / immunology
  • Humans
  • Immunoglobulin Class Switching*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Molecular Sequence Data
  • Promoter Regions, Genetic*
  • Protein Binding
  • Recombination, Genetic*
  • Response Elements
  • Sequence Alignment
  • Somatic Hypermutation, Immunoglobulin*
  • Transcriptional Activation

Substances

  • Estrogen Receptor alpha
  • Estrogens
  • HOXC4 protein, human
  • Homeodomain Proteins
  • Hoxc4 protein, mouse
  • AICDA (activation-induced cytidine deaminase)
  • Cytidine Deaminase