Germline deletion of Igh 3′ regulatory region elements hs 5, 6, 7 (hs5-7) affects B cell-specific regulation, rearrangement, and insulation of the Igh locus

Sabrina A. Volpi, Jiyoti Verma-Gaur, Rabih Hassan, Zhongliang Ju, Sergio Roa, Sanjukta Chatterjee, Uwe Werling, Harry Hou, Britta Will, Ulrich Steidl, Matthew Scharff, Winfried Edelman, Ann J Feeney, Barbara K Birshtein

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33 Citations (Scopus)

Abstract

Regulatory elements located within an ∼28-kb region 3′ of the Igh gene cluster (39 regulatory region) are required for class switch recombination and for high levels of IgH expression in plasma cells. We previously defined novel DNase I hypersensitive sites (hs) 5, 6, 7 immediately downstream of this region. The hs 5-7 region (hs5-7) contains a high density of binding sites for CCCTC-binding factor (CTCF), a zinc finger protein associated with mammalian insulator activity, and is an anchor for interactions with CTCF sites flanking the D H region. To test the function of hs5-7, we generated mice with an 8-kb deletion encompassing all three hs elements. B cells from hs5-7 knockout (KO) (hs5-7KO) mice showed a modest increase in expression of the nearest downstream gene. In addition, Igh alleles in hs5-7KO mice were in a less contracted configuration compared with wild-type Igh alleles and showed a 2-fold increase in the usage of proximal V H7183 gene families. Hs5-7KO mice were essentially indistinguishable from wild-type mice in B cell development, allelic regulation, class switch recombination, and chromosomal looping. We conclude that hs5-7, a high-density CTCF-binding region at the 3′ end of the Igh locus, impacts usage of V H regions as far as 500 kb away.

Original languageEnglish
Pages (from-to)2556-2566
Number of pages11
JournalJournal of Immunology
Volume188
Issue number6
DOIs
Publication statusPublished - 15 Mar 2012
Externally publishedYes

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