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¹ Laboratory of Hematopoiesis and Leukemogenesis, ² Laboratory of the Molecular Biology of B Cells, and ³ Department of Cancer Biology, Institut de Génétique et de Biologie Moléculaire et Cellulaire, 67400 Illkirch, France
⁴ Institut National de la Santé et de la Recherche Médicale U964, 67400 Illkirch, France
⁵ Centre National de la Recherche Scientifique UMR7104, 67400 Illkirch, France
⁶ Université de Strasbourg, 67000 Strasbourg, France

CORRESPONDENCE Susan Chan: scpk{at}igbmc.fr OR Philippe Kastner: scpk{at}igbmc.fr

Class switch recombination (CSR) allows the humoral immune response to exploit different effector pathways through specific secondary antibody isotypes. However, the molecular mechanisms and factors that control immunoglobulin (Ig) isotype choice for CSR are unclear. We report that deficiency for the Ikaros transcription factor results in increased and ectopic CSR to IgG_2b and IgG_2a, and reduced CSR to all other isotypes, regardless of stimulation. Ikaros suppresses active chromatin marks, transcription, and activation-induced cytidine deaminase (AID) accessibility at the 2b and 2a genes to inhibit class switching to these isotypes. Further, Ikaros directly regulates isotype gene transcription as it directly binds the Igh 3' enhancer and interacts with isotype gene promoters. Finally, Ikaros-mediated repression of 2b and 2a transcription promotes switching to other isotype genes by allowing them to compete for AID-mediated recombination at the single-cell level. Thus, our results reveal transcriptional competition between constant region genes in individual cells to be a critical and general mechanism for isotype specification during CSR. We show that Ikaros is a master regulator of this competition.

Abbreviations used: 3C, chromosome conformation capture; AcH3, histone H3 acetylation; AID, activation-induced cytidine deaminase; ChIP, chromatin immunoprecipitation; CSR, class switch recombination; DSB, double-stranded DNA break; GLT, germline transcript; HDAC, histone deacetylase; HS, hypersensitive; I, intronic; NGFR, nerve growth factor receptor; qPCR, quantitative PCR; S, switch; SC, single cell.

© 2009 Sellars et al.
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This article has been cited by other articles:

• Cai, Q., Dierich, A., Oulad-Abdelghani, M., Chan, S., Kastner, P. (2009). Helios Deficiency Has Minimal Impact on T Cell Development and Function. J. Immunol. 183: 2303-2311 [Abstract] [Full Text]  
• Sellars, M., Reina-San-Martin, B., Kastner, P., Chan, S. (2009). Ikaros controls isotype selection during immunoglobulin class switch recombination. JCB 185: i10-i10 [Full Text]  

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