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Long-Range Interactions between Three Transcriptional Enhancers, Active V Gene Promoters, and a 3' Boundary Sequence Spanning 46 Kilobases

Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas

Received 26 May 2004/ Returned for modification 27 July 2004/ Accepted 18 January 2005

The mouse immunoglobulin kappa (Ig) gene contains an intronic enhancer and two enhancers downstream of its transcription unit. Using chromosome conformation capture technology, we demonstrate that rearranged and actively transcribed Ig alleles in MPC-11 plasmacytoma cells exhibit mutual interactions over 22 kb between these three enhancers and V gene promoters. In addition, the 5' region of the active transcription unit exhibits a continuum of interactions with downstream chromatin segments. We also observe interactions between Ei and E3' with 3' boundary sequences 24 kb downstream of Ed, adjacent to a neighboring housekeeping gene. Very similar interactions between the enhancers are also exhibited by normal B cells isolated from mouse splenic tissue but not by germ line transcriptionally inactive alleles of T cells or P815 mastocytoma cells, which exhibit a seemingly linear chromatin organization. These results fit a looping mechanism for enhancer function like in the ß-globin locus and suggest a dynamic modulation of the spatial organization of the active Ig locus. Chromatin immunoprecipitation experiments reveal that the interacting Ig gene cis-acting sequences are associated with AP-4, E47, and p65NF-B, potential protein candidates that may be responsible for initiating and/or maintaining the formation of these higher-order complexes. However, S107 plasmacytoma cells that lack NF-B still exhibit mutual interactions between the Ig gene enhancers.

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