Please use this identifier to cite or link to this item:http://hdl.handle.net/20.500.12105/5186
CCCTC-Binding Factor Locks Premature IgH Germline Transcription and Restrains Class Switch Recombination
Front Immunol. 2017; 8:1076
In response to antigenic stimulation B cells undergo class switch recombination (CSR) at the immunoglobulin heavy chain (IgH) to replace the primary IgM/IgD isotypes by IgG, IgE, or IgA. CSR is initiated by activation-induced cytidine deaminase (AID) through the deamination of cytosine residues at the switch (S) regions of IgH. B cell stimulation promotes germline transcription (GLT) of specific S regions, a necessary event prior to CSR because it facilitates AID access to S regions. Here, we show that CCCTC-binding factor (CTCF)-deficient mice are severely impaired in the generation of germinal center B cells and plasma cells after immunization in vivo, most likely due to impaired cell survival. Importantly, we find that CTCF-deficient B cells have an increased rate of CSR under various stimulation conditions in vitro. This effect is not secondary to altered cell proliferation or AID expression in CTCF-deficient cells. Instead, we find that CTCF-deficient B cells harbor an increased mutation frequency at switch regions, probably reflecting an increased accessibility of AID to IgH in the absence of CTCF. Moreover, CTCF deficiency triggers premature GLT of S regions in naive B cells. Our results indicate that CTCF restricts CSR by enforcing GLT silencing and limiting AID access to IgH.
class switch recombination | CCCTC-binding factor | germline transcription | activation-induced deaminase | somatic hypermutation | ACTIVATION-INDUCED DEAMINASE | S-MU REGION | SOMATIC HYPERMUTATION | V(D)J RECOMBINATION | FACTOR CTCF | B-CELLS | LOCUS | ELEMENTS | AID | GENES
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