title: Flexible long-range loops in the VH gene region of the Igh locus facilitate the generation of a diverse antibody repertoire.
abstract: The immunoglobulin heavy-chain (Igh) locus undergoes large-scale contraction in pro-B cells, which facilitates VH-DJH recombination by juxtaposing distal VH genes next to the DJH-rearranged gene segment in the 3' proximal Igh domain. By using high-resolution mapping of long-range interactions, we demonstrate that local interaction domains established the three-dimensional structure of the extended Igh locus in lymphoid progenitors. In pro-B cells, these local domains engaged in long-range interactions across the Igh locus, which depend on the regulators Pax5, YY1, and CTCF. The large VH gene cluster underwent flexible long-range interactions with the more rigidly structured proximal domain, which probably ensures similar participation of all VH genes in VH-DJH recombination to generate a diverse antibody repertoire. These long-range interactions appear to be an intrinsic feature of the VH gene cluster, because they are still generated upon mutation of the Eμ enhancer, IGCR1 insulator, or 3' regulatory region in the proximal Igh domain.
authors: Research Institute of Molecular Pathology, Vienna Biocenter, Dr. Bohr-Gasse 7, 1030 Vienna, Austria.
authors: Jasna
authors: J
authors: Medvedovic
authors: Anja
authors: A
authors: Ebert
authors: Hiromi
authors: H
authors: Tagoh
authors: Ido M
authors: IM
authors: Tamir
authors: Tanja A
authors: TA
authors: Schwickert
authors: Maria
authors: M
authors: Novatchkova
authors: Qiong
authors: Q
authors: Sun
authors: Pim J
authors: PJ
authors: Huis In 't Veld
authors: Chunguang
authors: C
authors: Guo
authors: Hye Suk
authors: HS
authors: Yoon
authors: Yves
authors: Y
authors: Denizot
authors: Sjoerd J B
authors: SJ
authors: Holwerda
authors: Wouter
authors: W
authors: de Laat
authors: Michel
authors: M
authors: Cogné
authors: Yang
authors: Y
authors: Shi
authors: Frederick W
authors: FW
authors: Alt
authors: Meinrad
authors: M
authors: Busslinger
mesh_terms: D000818:Animals; D000916:Antibody Diversity / Q000235:genetics*; D001483:Base Sequence; D001665:Binding Sites; D000076246:CCCTC-Binding Factor; D002874:Chromosome Mapping; D015321:Gene Rearrangement; D015326:Gene Rearrangement, B-Lymphocyte, Heavy Chain / Q000235:genetics*; D050438:Genes, Immunoglobulin Heavy Chain; D007135:Immunoglobulin Variable Region / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D051757:PAX5 Transcription Factor / Q000378:metabolism; D054448:Precursor Cells, B-Lymphoid / Q000276:immunology*; D011485:Protein Binding; D012097:Repressor Proteins / Q000378:metabolism; D017422:Sequence Analysis, DNA; D050986:YY1 Transcription Factor / Q000378:metabolism
chemical_list: D000076246:CCCTC-Binding Factor; C000619698:Ctcf protein, mouse; D007135:Immunoglobulin Variable Region; D051757:PAX5 Transcription Factor; C497282:Pax5 protein, mouse; D012097:Repressor Proteins; D050986:YY1 Transcription Factor; C494699:Yy1 protein, mouse
references: Nature. 2009 Jul 16;460(7253):410-3
references: 19458616
references: Cell. 1993 Jun 18;73(6):1155-64
references: 8513499
references: EMBO J. 2012 Jun 05;31(14):3130-46
references: 22669466
references: Cell. 2011 Oct 14;147(2):332-43
references: 21982154
references: Genes Dev. 2004 Feb 15;18(4):411-22
references: 15004008
references: Genes Dev. 2003 Jan 1;17(1):37-42
references: 12514097
references: Nature. 2012 Apr 11;485(7398):381-5
references: 22495304
references: Methods Enzymol. 2012;513:89-112
references: 22929766
references: Science. 2002 Apr 5;296(5565):158-62
references: 11935030
references: Genes Dev. 2006 Sep 1;20(17):2349-54
references: 16951251
references: Nature. 2012 Apr 11;485(7398):376-80
references: 22495300
references: Proc Natl Acad Sci U S A. 2005 Oct 4;102(40):14362-7
references: 16186486
references: PLoS Genet. 2009 Nov;5(11):e1000739
references: 19956766
references: Nature. 2011 Sep 11;477(7365):424-30
references: 21909113
references: Adv Immunol. 2008;99:1-32
references: 19117530
references: J Immunol. 2006 Feb 15;176(4):2439-47
references: 16456003
references: Nat Immunol. 2005 Jan;6(1):31-41
references: 15580273
references: Genes Dev. 2005 Feb 1;19(3):322-7
references: 15687256
references: Proc Natl Acad Sci U S A. 2011 Jun 7;108(23):9566-71
references: 21606361
references: Proc Natl Acad Sci U S A. 1991 Nov 1;88(21):9804-8
references: 1946405
references: J Immunol. 2006 Apr 1;176(7):4221-34
references: 16547259
references: EMBO J. 2011 May 06;30(12):2388-404
references: 21552207
references: Genes Dev. 2007 May 15;21(10):1179-89
references: 17504937
references: Nat Immunol. 2009 Jun;10(6):655-64
references: 19448632
references: Immunity. 2011 Feb 25;34(2):175-87
references: 21349430
references: Blood. 2010 Sep 16;116(11):1895-8
references: 20538806
references: Proc Natl Acad Sci U S A. 2012 Oct 16;109(42):17004-9
references: 23027941
references: Mol Cell Biol. 2005 Feb;25(4):1511-25
references: 15684400
references: Nat Immunol. 2004 Jun;5(6):630-7
references: 15107847
references: Cell. 2009 Aug 7;138(3):435-48
references: 19665968
references: Nat Methods. 2007 Nov;4(11):895-901
references: 17971780
references: Nat Protoc. 2007;2(7):1722-33
references: 17641637
references: J Exp Med. 2009 May 11;206(5):1019-27
references: 19414554
references: Cell. 2008 Apr 18;133(2):265-79
references: 18423198
references: Nat Immunol. 2012 Dec;13(12):1196-204
references: 23064439