CCCTC-Binding Factor Locks Premature IgH Germline Transcription and Restrains Class Switch Recombination

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 t...

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Veröffentlicht in:Frontiers in immunology Jg. 8; S. 1076
Hauptverfasser: Marina-Zárate, Ester, Pérez-García, Arantxa, Ramiro, Almudena R.
Format: Journal Article
Sprache:Englisch
Veröffentlicht: Switzerland Frontiers Media S.A 04.09.2017
Schlagworte:
activation-induced deaminase
CCCTC-binding factor
class switch recombination
germline transcription
Immunology
somatic hypermutation
CCCTC-binding factor
somatic hypermutation
class switch recombination
germline transcription
activation-induced deaminase
ISSN:1664-3224, 1664-3224
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Zusammenfassung: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 , 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 . 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 naïve B cells. Our results indicate that CTCF restricts CSR by enforcing GLT silencing and limiting AID access to IgH.
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Reviewed by: Michael Zemlin, Universitätsklinikum des Saarlandes, Germany; Paolo Casali, The University of Texas Health Science Center San Antonio, United States
Edited by: Deborah K. Dunn-Walters, University of Surrey, United Kingdom
Present address: Arantxa Pérez-García, Epigenetics of Cancer and Ageing Group, Cancer Research UK Beatson Institute, Glasgow, United Kingdom
These authors have contributed equally to this work.
Specialty section: This article was submitted to B Cell Biology, a section of the journal Frontiers in Immunology
ISSN:1664-3224
1664-3224
DOI:10.3389/fimmu.2017.01076