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 G. Steidl, Matthew D. Scharff, Winfried Edelmann, Ann J. Feeney, Barbara K. Birshtein

Research output: Contribution to journalArticle

24 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 (US)
Pages (from-to)2556-2566
Number of pages11
JournalJournal of Immunology
Volume188
Issue number6
DOIs
StatePublished - Mar 15 2012

Fingerprint

Nucleic Acid Regulatory Sequences
B-Lymphocytes
Knockout Mice
Genetic Recombination
Alleles
Deoxyribonuclease I
Zinc Fingers
Multigene Family
Plasma Cells
Genes
Binding Sites
Proteins

ASJC Scopus subject areas

  • Immunology

Cite this

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

In: Journal of Immunology, Vol. 188, No. 6, 15.03.2012, p. 2556-2566.

Research output: Contribution to journalArticle

Volpi, Sabrina A. ; Verma-Gaur, Jiyoti ; Hassan, Rabih ; Ju, Zhongliang ; Roa, Sergio ; Chatterjee, Sanjukta ; Werling, Uwe ; Hou, Harry ; Will, Britta ; Steidl, Ulrich G. ; Scharff, Matthew D. ; Edelmann, Winfried ; Feeney, Ann J. ; Birshtein, Barbara K. / 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. In: Journal of Immunology. 2012 ; Vol. 188, No. 6. pp. 2556-2566.
@article{fbf18a885a354be68ace8f0dbb5e96cf,
title = "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",
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.",
author = "Volpi, {Sabrina A.} and Jiyoti Verma-Gaur and Rabih Hassan and Zhongliang Ju and Sergio Roa and Sanjukta Chatterjee and Uwe Werling and Harry Hou and Britta Will and Steidl, {Ulrich G.} and Scharff, {Matthew D.} and Winfried Edelmann and Feeney, {Ann J.} and Birshtein, {Barbara K.}",
year = "2012",
month = "3",
day = "15",
doi = "10.4049/jimmunol.1102763",
language = "English (US)",
volume = "188",
pages = "2556--2566",
journal = "Journal of Immunology",
issn = "0022-1767",
publisher = "American Association of Immunologists",
number = "6",

}

TY - JOUR

T1 - 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

AU - Volpi, Sabrina A.

AU - Verma-Gaur, Jiyoti

AU - Hassan, Rabih

AU - Ju, Zhongliang

AU - Roa, Sergio

AU - Chatterjee, Sanjukta

AU - Werling, Uwe

AU - Hou, Harry

AU - Will, Britta

AU - Steidl, Ulrich G.

AU - Scharff, Matthew D.

AU - Edelmann, Winfried

AU - Feeney, Ann J.

AU - Birshtein, Barbara K.

PY - 2012/3/15

Y1 - 2012/3/15

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84857812660&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84857812660&partnerID=8YFLogxK

U2 - 10.4049/jimmunol.1102763

DO - 10.4049/jimmunol.1102763

M3 - Article

C2 - 22345664

AN - SCOPUS:84857812660

VL - 188

SP - 2556

EP - 2566

JO - Journal of Immunology

JF - Journal of Immunology

SN - 0022-1767

IS - 6

ER -