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Transcription of a Productively Rearranged Ig VDJC Does Not Require the Presence of HS4 in the Igh 3' Regulatory Region¹

Department of Biological Sciences, Hunter College and Graduate Center of The City University of New York, New York, NY 10021

V gene assembly, class switch recombination, and somatic hypermutation are gene-modifying processes essential to the development of an effective Ab response. If inappropriately applied, however, these processes can mediate genetic changes that lead to disease (e.g., lymphoma). A series of control elements within the Ig H chain (Igh) locus has been implicated in regulating these processes as well as in regulating IgH gene transcription. These include the intronic enhancer (Eµ) and several elements at the 3' end of the locus (hs1,2, hs3a, hs3b, and hs4) known collectively as the 3' regulatory region. Although it is clear that the Eµ plays a unique role in V gene assembly, it has not been established whether there are unique functions for each element within the 3' regulatory region. In earlier studies in mice and in mouse cell lines, pairwise deletion of hs3b and hs4 had a dramatic effect on both class switch recombination and IgH gene transcription; deletion of an element almost identical with hs3b (hs3a), however, yielded no discernible phenotype. To test the resulting hypothesis that hs4 is uniquely required for these processes, we induced the deletion of hs4 within a bacterial artificial chromosome transgene designed to closely approximate the 3' end of the natural Igh locus. When introduced into an Ig-secreting cell line, an Ig transcription unit within the bacterial artificial chromosome was expressed efficiently and the subsequent deletion of hs4 only moderately affected Ig expression. Thus, hs4 does not play a uniquely essential role in the transcription of a productively rearranged Ig VDJC transcription unit.

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 AI30653 (to L.A.E.). The infrastructure and instrumentation at Hunter College are supported in part by a Research Centers in Minority Institutions award from the National Institutes of Health (RR-0307).

² Address correspondence and reprint requests to Dr. Laurel Eckhardt, Hunter College, 695 Park Avenue, New York, NY 10021. E-mail address: eckhardt{at}genectr.hunter.cuny.edu

³ Abbreviations used in this paper: CSR, class switch recombination; BAC, bacterial artificial chromosome; CRE, cyclization recombination enzyme; EGFP, enhanced GFP; 3'RR, 3' regulatory region of the IgH locus.

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