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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 Eµ{triangledown} ,{ddagger}

Daniel J. Bolland,1 Andrew L. Wood,1 Roshi Afshar,2 Karen Featherstone,1 Eugene M. Oltz,2 and Anne E. Corcoran1*

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 VH region in pro-B cells, remodels chromatin for VH-to-DJH recombination. Using RNA fluorescence in situ hybridization, we now show that antisense intergenic transcription occurs throughout the Igh DHJH 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 Eµ and is abrogated in mice lacking this enhancer, indicating that Eµ regulates DH antisense transcription. Eµ was recently demonstrated to regulate DH-to-JH recombination of the Igh locus. Together, these data suggest that Eµ controls DH-to-JH recombination by activating this form of germ line Igh transcription, thus providing a long-range, processive mechanism by which Eµ can regulate chromatin accessibility throughout the DH region. In contrast, Eµ deletion has no effect on VH antisense intergenic transcription, which is rarely associated with DH 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.

* Corresponding author. Mailing address: Laboratory of Chromatin and Gene Expression, Babraham Institute, Babraham Research Campus, Cambridge CB22 3AT, United Kingdom. Phone: 44 1223 496397. Fax: 44 1223 496022. E-mail: anne.corcoran{at}bbsrc.ac.uk

{triangledown} Published ahead of print on 25 May 2007.

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

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.



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