Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 114, Issue 23, Pages 6092-6097Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1701631114
Keywords
B lymphocyte; IgH locus; insulator; germline transcription; class switch recombination
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Funding
- Institut National du Cancer Grant [INCA_9363/PLBIO15-134]
- Agence Nationale de la Recherche [ANR-16-CE12-0017]
- Fondation ARC pour la Recherche sur le Cancer [PJA 20141201647]
- Ligue Contre le Cancer-Comite de Haute-Garonne
- Canceropole Grand Sud-Ouest
- Agence Nationale de la Recherche (ANR) [ANR-16-CE12-0017] Funding Source: Agence Nationale de la Recherche (ANR)
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Class switch recombination (CSR) plays an important role in adaptive immune response by enabling mature B cells to switch from IgM expression to the expression of downstream isotypes. CSR is preceded by inducible germline (GL) transcription of the constant genes and is controlled by the 3' regulatory region (3'RR) in a stimulus-dependent manner. Why the 3'RR-mediated up-regulation of GL transcription is delayed to the mature B-cell stage is presently unknown. Here we show that mice devoid of an inducible CTCF binding element, located in the a constant gene, display a marked isotype-specific increase of GL transcription in developing and resting splenic B cells and altered CSR in activated B cells. Moreover, insertion of a GL promoter downstream of the CTCF insulator led to premature activation of the ectopic promoter. This study provides functional evidence that the 3'RR has a developmentally controlled potential to constitutively activate GL promoters but that this activity is delayed, at least in part, by the CTCF insulator, which borders a transcriptionally active domain established by the 3'RR in developing B cells.
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