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Requirement for Enhancer Specificity in Immunoglobulin Heavy Chain Locus Regulation¹

Igor I. Kuzin^*, Ludmila Bagaeva, Faith M. Young^*,, and Andrea Bottaro^2,*,,

^* Department of Medicine, Department of Neurology, Department of Microbiology and Immunology, and J. P. Wilmot Cancer Center, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642

The intronic Eµ enhancer has been implicated in IgH locus transcription, VDJ recombination, class switch recombination, and somatic hypermutation. How Eµ controls these diverse mechanisms is still largely unclear, but transcriptional enhancer activity is thought to play a central role. In this study we compare the phenotype of mice lacking the Eµ element (Eµ) with that of mice in which Eµ was replaced with the ubiquitous SV40 transcriptional enhancer (SV40eR mutation) and show that SV40e cannot functionally complement Eµ loss in pro-B cells. Surprisingly, in fact, the SV40eR mutation yields a more profound defect than Eµ, with an almost complete block in µ0 germline transcription in pro-B cells. This active transcriptional suppression caused by enhancer replacement appears to be specific to the early stages of B cell development, as mature SV40eR B cells express µ0 transcripts at higher levels than Eµ mice and undergo complete DNA demethylation at the IgH locus. These results indicate an unexpectedly stringent, developmentally restricted requirement for enhancer specificity in regulating IgH function during the early phases of B cell differentiation, consistent with the view that coordination of multiple independent regulatory mechanisms and elements is essential for locus activation and VDJ recombination.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grant R01 AI45012 (to A.B.).

² Address correspondence and reprint requests to Dr. Andrea Bottaro, University of Rochester Medical Center 695, University of Rochester School of Medicine, 601 Elmwood Avenue, Rochester, NY 14642. E-mail address: andrea_bottaro{at}urmc.rochester.edu

³ Abbreviations used in this paper: MAR, matrix attachment region; BM, bone marrow; CSR, class switch recombination; ES, embryonic stem; LTBMC, long-term BM culture; pgk, phosphoglycerate kinase; qPCR, quantitative real-time PCR; SHM, somatic hypermutation.

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