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J. Biol. Chem., Vol. 282, Issue 48, 35169-35178, November 30, 2007

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Evidence for Physical Interaction between the Immunoglobulin Heavy Chain Variable Region and the 3' Regulatory Region^*

From the Department of Cell Biology, Albert Einstein College of Medicine, Bronx, New York 10461

B cell-specific expression of immunoglobulin heavy chain (IgH) genes utilizes two cis regulatory regions, the intronic enhancer (Eµ), located in the J_H-Cµ intron, and a complex regulatory region that lies 3' to the IgH gene cluster, 3' RR. We hypothesized that the 3' RR is involved in IgH gene transcription in plasma cells via physical interaction between distal 3' RR enhancers and target V_H sequences, with loop formation by intervening DNA. In support of this hypothesis we report sequence data at DNA recombination breakpoints as evidence for loop formation preceding DNA inversion in a plasma cell line. In addition, using the chromosome conformation capture technique, physical interactions between V_H and 3' RR were analyzed directly and detected in MPC11 plasma cells and variants and normal splenic B cells but not detected in splenic T cells or in non-B cells. V_H-3' RR interactions were present in the absence of Eµ, but when the hs1,2 enhancer was replaced by a Neo^R gene in a variant cell line lacking Eµ, H chain expression was lost, and interactions between V_H and 3' RR and among the 3' RR regulators themselves were severely disrupted. In addition, the chromosome conformation capture technique detected interactions between the myc promoter and 3' RR elements in MPC11, which like other plasmacytomas contains a reciprocal translocation between the c-myc and the IgH locus. In sum, our data support a hypothesis that cis V_H-3' RR and myc-3' RR interactions involve physical interactions between these DNA elements.

Received for publication, July 12, 2007 , and in revised form, October 1, 2007.

^* This work was supported in part by National Institutes of Health Grant AI13509 (to B. K. B.) and Albert Einstein Cancer Grant P30 CA13330. 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Table S1 and Figs. S1-S3.

¹ Supported in part by National Institutes of Health 5T32 CA09173.

² Current address: Dept. of Internal Medicine, University of Pittsburgh Medical Center (UPMC McKeesport), 1500 Fifth Ave., McKeesport, PA 15132.

³ Current address: GlaxoSmithKline Biologicals, Research & Development, rue de l'Institut, 89 B-1330, Rixensart, Belgium.

⁴ To whom correspondence and reprint requests should be addressed: Dept. of Cell Biology, Albert Einstein College of Medicine, 1300 Morris Park Ave., Bronx, NY 10461. Tel.: 718-430-2291; Fax: 718-430-8574; E-mail: birshtei{at}aecom.yu.edu.

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