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Molecular and Cellular Biology, August 2007, p. 5523-5533, Vol. 27, No. 15
0270-7306/07/$08.00+0     doi:10.1128/MCB.02407-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Antisense Intergenic Transcription Precedes Igh D-to-J Recombination and Is Controlled by the Intronic Enhancer E_µ ^,

Laboratory of Chromatin and Gene Expression, Babraham Institute, Babraham Research Campus, Cambridge CB22 3AT, United Kingdom,¹ Department of Microbiology/Immunology, Vanderbilt University Medical School, Nashville, Tennessee 37232²

Received 22 December 2006/ Returned for modification 2 February 2007/ Accepted 16 May 2007

V(D)J recombination is believed to be regulated by alterations in chromatin accessibility to the recombinase machinery, but the mechanisms responsible remain unclear. We previously proposed that antisense intergenic transcription, activated throughout the mouse Igh V_H region in pro-B cells, remodels chromatin for V_H-to-DJ_H recombination. Using RNA fluorescence in situ hybridization, we now show that antisense intergenic transcription occurs throughout the Igh D_HJ_H region before D-to-J recombination, indicating that this is a widespread process in V(D)J recombination. Transcription initiates near the Igh intronic enhancer E_µ and is abrogated in mice lacking this enhancer, indicating that E_µ regulates D_H antisense transcription. E_µ was recently demonstrated to regulate D_H-to-J_H recombination of the Igh locus. Together, these data suggest that E_µ controls D_H-to-J_H recombination by activating this form of germ line Igh transcription, thus providing a long-range, processive mechanism by which E_µ can regulate chromatin accessibility throughout the D_H region. In contrast, E_µ deletion has no effect on V_H antisense intergenic transcription, which is rarely associated with D_H antisense transcription, suggesting differential regulation and separate roles for these processes at sequential stages of V(D)J recombination. These results support a directive role for antisense intergenic transcription in enabling access to the recombination machinery.

Published ahead of print on 25 May 2007.

Supplemental material for this article may be found at http://mcb.asm.org/.

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