title: The in vivo pattern of binding of RAG1 and RAG2 to antigen receptor loci.
abstract: The critical initial step in V(D)J recombination, binding of RAG1 and RAG2 to recombination signal sequences flanking antigen receptor V, D, and J gene segments, has not previously been characterized in vivo. Here, we demonstrate that RAG protein binding occurs in a highly focal manner to a small region of active chromatin encompassing Ig kappa and Tcr alpha J gene segments and Igh and Tcr beta J and J-proximal D gene segments. Formation of these small RAG-bound regions, which we refer to as recombination centers, occurs in a developmental stage- and lineage-specific manner. Each RAG protein is independently capable of specific binding within recombination centers. While RAG1 binding was detected only at regions containing recombination signal sequences, RAG2 binds at thousands of sites in the genome containing histone 3 trimethylated at lysine 4. We propose that recombination centers coordinate V(D)J recombination by providing discrete sites within which gene segments are captured for recombination.
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, 300 Cedar Street, Box 208011, New Haven, CT 06520-8011, USA.
authors.forename: Yanhong
authors.initials: Y
authors.lastname: Ji
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Resch
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Corbett
authors.forename: Arito
authors.initials: A
authors.lastname: Yamane
authors.forename: Rafael
authors.initials: R
authors.lastname: Casellas
authors.forename: David G
authors.initials: DG
authors.lastname: Schatz
mesh_terms: D000818:Animals; D004268:DNA-Binding Proteins / Q000378:metabolism*; D015322:Gene Rearrangement, B-Lymphocyte; D015329:Gene Rearrangement, T-Lymphocyte; D050438:Genes, Immunoglobulin Heavy Chain; D019673:Genes, T-Cell Receptor alpha; D019674:Genes, T-Cell Receptor beta; D018398:Homeodomain Proteins / Q000378:metabolism*; D007145:Immunoglobulin kappa-Chains / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011995:Recombination, Genetic
chemical_list: D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; D007145:Immunoglobulin kappa-Chains; C499308:Rag2 protein, mouse; C064658:RAG-1 protein
references.citation: J Immunol. 2008 Feb 15;180(4):2339-46
references.pmid: 18250443
references.citation: Cell. 2008 Dec 12;135(6):1130-42
references.pmid: 19070581
references.citation: Immunity. 1997 Mar;6(3):225-33
references.pmid: 9075923
references.citation: Immunity. 1999 Mar;10(3):313-22
references.pmid: 10204487
references.citation: Nature. 2004 Mar 4;428(6978):88-93
references.pmid: 14999286
references.citation: Immunol Rev. 2003 Aug;194:77-95
references.pmid: 12846809
references.citation: Nat Immunol. 2005 Dec;6(12):1272-9
references.pmid: 16286921
references.citation: Nucleic Acids Res. 2008 Apr;36(6):2060-72
references.pmid: 18281312
references.citation: Mol Cell. 2005 Jun 10;18(6):699-709
references.pmid: 15949444
references.citation: Mol Cell Biol. 1995 Oct;15(10):5657-70
references.pmid: 7565717
references.citation: DNA Repair (Amst). 2006 Sep 8;5(9-10):1246-58
references.pmid: 16798110
references.citation: Proc Natl Acad Sci U S A. 2007 Oct 23;104(43):17046-51
references.pmid: 17939999
references.citation: Immunol Rev. 2004 Aug;200:70-82
references.pmid: 15242397
references.citation: Cell. 2008 Apr 18;133(2):265-79
references.pmid: 18423198
references.citation: Nature. 2007 Sep 27;449(7161):483-6
references.pmid: 17898768
references.citation: Annu Rev Biochem. 2002;71:101-32
references.pmid: 12045092
references.citation: EMBO J. 2002 Aug 1;21(15):4162-71
references.pmid: 12145216
references.citation: Genes Dev. 1999 Dec 1;13(23):3070-80
references.pmid: 10601033
references.citation: PLoS Biol. 2005 Jun;3(6):e181
references.pmid: 15898832
references.citation: Mol Cell. 2007 Jan 12;25(1):15-30
references.pmid: 17218268
references.citation: Mol Cell. 1998 Dec;2(6):829-39
references.pmid: 9885570
references.citation: Science. 1999 Aug 13;285(5430):1080-4
references.pmid: 10446057
references.citation: Immunity. 2007 Oct;27(4):561-71
references.pmid: 17936034
references.citation: Immunogenetics. 2004 Sep;56(6):399-404
references.pmid: 15322776
references.citation: Adv Immunol. 2006;91:45-109
references.pmid: 16938538
references.citation: Nat Immunol. 2007 Jul;8(7):687-94
references.pmid: 17579647
references.citation: DNA Repair (Amst). 2006 Sep 8;5(9-10):1234-45
references.pmid: 16793349
references.citation: Eur J Immunol. 2008 Sep;38(9):2564-72
references.pmid: 18792409
references.citation: Nat Immunol. 2009 Aug;10(8):817-21
references.pmid: 19621044
references.citation: Nat Immunol. 2009 Jun;10(6):655-64
references.pmid: 19448632
references.citation: Mol Cell. 2000 Jan;5(1):97-107
references.pmid: 10678172
references.citation: Proc Natl Acad Sci U S A. 2007 Jan 16;104(3):903-7
references.pmid: 17210914
references.citation: Cell. 1989 Sep 22;58(6):1035-46
references.pmid: 2476238
references.citation: EMBO J. 1999 Jul 1;18(13):3712-23
references.pmid: 10393186
references.citation: Annu Rev Immunol. 2006;24:541-70
references.pmid: 16551259
references.citation: Nature. 2007 Dec 13;450(7172):1106-10
references.pmid: 18033247
references.citation: Cell. 2004 Apr 16;117(2):171-84
references.pmid: 15084256
references.citation: J Immunol. 1994 Apr 1;152(7):3467-75
references.pmid: 7511648
references.citation: Cell. 1996 Jun 14;85(6):887-97
references.pmid: 8681383
references.citation: Nature. 2006 Jul 27;442(7101):466-70
references.pmid: 16799570
references.citation: Cell. 2007 May 18;129(4):823-37
references.pmid: 17512414
references.citation: Mol Cell. 2010 Jan 29;37(2):282-93
references.pmid: 20122409
references.citation: Genes Dev. 1999 Dec 1;13(23):3059-69
references.pmid: 10601032
references.citation: Immunol Rev. 2004 Aug;200:90-114
references.pmid: 15242399
references.citation: Nat Struct Mol Biol. 2009 May;16(5):499-508
references.pmid: 19396172
references.citation: Cell. 1995 Nov 3;83(3):387-95
references.pmid: 8521468
references.citation: Proc Natl Acad Sci U S A. 2007 Mar 6;104(10):4002-7
references.pmid: 17360467
references.citation: Mol Cell. 2007 Sep 7;27(5):842-50
references.pmid: 17803947
references.citation: Mol Cell Biol. 2002 Jan;22(1):69-77
references.pmid: 11739723
references.citation: Mol Cell. 2009 Jun 12;34(5):535-44
references.pmid: 19524534