HoxC4 binds to the promoter of the cytidine deaminase AID gene to induce AID expression, class-switch DNA recombination and somatic hypermutation

Abstract

AID is critical for immunoglobulin class switch DNA recombination (CSR) and somatic hypermutation (SHM). Here we showed that AID expression was induced by the HoxC4 homeodomain transcription factor, which bound to a highly conserved HoxC4-Oct site in the Aicda promoter. This site functioned in synergy with a conserved Sp-NF-κB-binding site. HoxC4 was preferentially expressed in germinal center B cells and was upregulated by CD154:CD40 engagement, lipopolysaccharide and interleukin-4. HoxC4 deficiency resulted in impaired CSR and SHM, due to decreased AID expression and not other putative HoxC4-dependent activity. Enforced expression of AID in Hoxc4 −/− B cells fully restored CSR. Thus, HoxC4 directly activates the Aicda promoter, thereby inducing AID expression, CSR and SHM.CSR and SHM are critical for the maturation of antibody responses to foreign and selfantigens. CSR recombines switch (S) region DNA located upstream of constant heavy chain (C H ) region exons, thereby changing immunoglobulin (Ig) C H regions and endowing antibodies with new biological effector functions. SHM introduces mainly point mutations in Ig variable regions, thereby providing the structural substrate for selection of higher affinity antibody mutants by antigen. In spite of the recent advances made in the identification of some factors involved in CSR and SHM, the intimate mechanisms of these processes remain elusive. Both CSR and SHM require activation-induced cytidine deaminase (AID), which is expressed by activated B cells, mainly in germinal centers (GCs) of peripheral lymphoid organs1,2. AID initiates CSR and SHM by deaminating dC residues to yield dU:dG mispairs in DNA3-8. These dU:dG mispairs trigger DNA repair processes entailing introduction of mutations in V(D)J regions or DNA breaks, including doublestranded DNA breaks, which lead to non-classic non-homologous end-joining and CSR3,5,9-14.Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms Correspondence should be addressed to P.C. (pcasali@uci.edu). 1 These authors contributed equally to this work. AUTHOR CONTRIBUTIONS H.Z. and S.-R.P. contributed equally to this work; S.-R.P., H.Z., Z.P., J.Z., T.M., E.J.P. and A.A.-Q. performed the experiments; Z.X. helped designing experiments, discussed the results and read and provided comments on the manuscript; H.Z. designed the experiments, analyzed the data and prepared the manuscript; P.C. designed the experiments, analyzed the data, supervised the work and prepared the manuscript. HHS Public Access Author Manuscript Author ManuscriptAuthor Manuscript Author ManuscriptThe mechanisms governing the transcriptional regulation of the gene encoding AID (AICDA in the human and Aicda in the mouse) remain to be elucidated. A conserved region in the first intron of Aicda containing two E-boxes, the consensus sequence for E2A (http:// www.signa...

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

“…After estrogen withdrawal, whereas HOXC5 and HOXC6 expression quickly returns to the prestimulation level, HOXC4 expression persists at a steady high level. HoxC4 expression is probably responsible for the estrogen-induced AID expression reported in MCF-7 cells (47), particularly in light of our demonstration of the critical role of HoxC4 in activating the AICDA/Aicda promoter in B cells (33,34,40). This prompted us to reconsider the suggestion that estrogen up-regulates AID gene expression through binding of ERs to the AICDA promoter (47).…”

“…As we have also shown, in both human and mouse B cells, HOXC4/HoxC4 expression is induced by GC differentiation-inducing stimuli, such as CD154 or LPS and IL-4, that are required for induction of AICDA/Aicda (human/ mouse activation-induced cytosine deaminase) expression (38 -40). The conserved homeodomain HoxC4 transcription factor is a critical activator of the AID gene promoter (40,41). HoxC4 binds directly to a highly conserved HoxC4/Oct site in the AICDA/Aicda promoter and activates this promoter in synergy with Oct-1/2, NF-B, and Sp1/Sp3 (40).…”

“…The conserved homeodomain HoxC4 transcription factor is a critical activator of the AID gene promoter (40,41). HoxC4 binds directly to a highly conserved HoxC4/Oct site in the AICDA/Aicda promoter and activates this promoter in synergy with Oct-1/2, NF-B, and Sp1/Sp3 (40).…”

Toll-like receptor signaling pathway in chronic lymphocytic leukemia: distinct gene expression profiles of potential pathogenic significance in specific subsets of patients

“…[11][12][13][14] The stimulation of surface or endosomal TLR leads to the activation of NF-kB and the induction of activationinduced cytidine deaminase, which, in combination with cytokines, induces class switch recombination to specific isotypes. [15][16][17] This depends on correct intracellular trafficking and localization of the engaged TLR and on the presence of other signals, such as those emanating from the BcR. 10,[18][19][20] The activation of B cells by TLR engagement may lead to a more efficient interaction with T cells and dendritic cells due to up-regulation of the co-stimulatory CD80 and MHCII molecules.…”

Activation-induced cytidine deaminase (AID) is necessary for the epithelial–mesenchymal transition in mammary epithelial cells

“…In addition, AID is present at low levels in pluripotent cells such as oocytes, embryonic germ cells, embryonic stem cells (6), and spermatocytes (7), where it may have a function beyond antibody gene diversification (8)(9)(10). AID expression is induced by inflammatory paracrine signals such as interleukin-4 (IL-4), tumor necrosis factor alpha (TNFα), and transforming growth factor beta (TGFβ) (11)(12)(13), and it has been detected in multiple epithelial tissues in association with chronic inflammatory conditions that promote tumorigenesis (14)(15)(16)(17)(18). AID is also expressed in experimentally transformed human mammary epithelial cells (19), and in several cancer cell lines including breast cancer (20,21).…”