Journal
MOLECULAR AND CELLULAR BIOLOGY
Volume 27, Issue 15, Pages 5523-5533Publisher
AMER SOC MICROBIOLOGY
DOI: 10.1128/MCB.02407-06
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Funding
- Biotechnology and Biological Sciences Research Council [BBS/E/B/0000C163] Funding Source: Medline
- NCI NIH HHS [R01 CA100905, CA100905, T32 CA09385, P30 CA068485, P30 CA68485, T32 CA009385] Funding Source: Medline
- NHLBI NIH HHS [P01 HL68744, P01 HL068744] Funding Source: Medline
- Biotechnology and Biological Sciences Research Council [BBS/E/B/0000C163] Funding Source: researchfish
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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(H)J(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-mu and is abrogated in mice lacking this enhancer, indicating that E-mu regulates D-H antisense transcription. E-mu was recently demonstrated to regulate D-H-to-J(H) recombination of the Igh locus. Together, these data suggest that E-mu 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-mu can regulate chromatin accessibility throughout the D-H region. In contrast, E-mu 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.
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