title: Extremely Long-Range Chromatin Loops Link Topological Domains to Facilitate a Diverse Antibody Repertoire.
abstract: Early B cell development is characterized by large-scale Igh locus contraction prior to V(D)J recombination to facilitate a highly diverse Ig repertoire. However, an understanding of the molecular architecture that mediates locus contraction remains unclear. We have combined high-resolution chromosome conformation capture (3C) techniques with 3D DNA FISH to identify three conserved topological subdomains. Each of these topological folds encompasses a major VH gene family that become juxtaposed in pro-B cells via megabase-scale chromatin looping. The transcription factor Pax5 organizes the subdomain that spans the VHJ558 gene family. In its absence, the J558 VH genes fail to associate with the proximal VH genes, thereby providing a plausible explanation for reduced VHJ558 gene rearrangements in Pax5-deficient pro-B cells. We propose that Igh locus contraction is the cumulative effect of several independently controlled chromatin subdomains that provide the structural infrastructure to coordinate optimal antigen receptor assembly.
authors.affiliation: Gene Regulation Section, Laboratory of Molecular Biology and Immunology, National Institute on Aging/National Institutes of Health, Baltimore, MD 21224, USA.
authors.forename: Lindsey
authors.initials: L
authors.lastname: Montefiori
authors.affiliation: Department of Microbiology and Immunology, University of Illinois College of Medicine, Chicago, IL 60612-7344, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Wuerffel
authors.affiliation: Department of Bioengineering, University of Illinois College of Engineering and College of Medicine, Chicago, IL 60612-7344, USA.
authors.forename: Damian
authors.initials: D
authors.lastname: Roqueiro
authors.affiliation: Howard Hughes Medical Institute and Program in Systems Biology, Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA 01605-0103, USA.
authors.forename: Bryan
authors.initials: B
authors.lastname: Lajoie
authors.affiliation: Gene Regulation Section, Laboratory of Molecular Biology and Immunology, National Institute on Aging/National Institutes of Health, Baltimore, MD 21224, USA.
authors.forename: Changying
authors.initials: C
authors.lastname: Guo
authors.affiliation: Gene Regulation Section, Laboratory of Molecular Biology and Immunology, National Institute on Aging/National Institutes of Health, Baltimore, MD 21224, USA.
authors.forename: Tatiana
authors.initials: T
authors.lastname: Gerasimova
authors.affiliation: Gene Expression and Genomics Unit, Laboratory of Genetics, National Institute on Aging/National Institutes of Health, Baltimore, MD 21224, USA.
authors.forename: Supriyo
authors.initials: S
authors.lastname: De
authors.affiliation: Gene Expression and Genomics Unit, Laboratory of Genetics, National Institute on Aging/National Institutes of Health, Baltimore, MD 21224, USA.
authors.forename: William
authors.initials: W
authors.lastname: Wood
authors.affiliation: Gene Expression and Genomics Unit, Laboratory of Genetics, National Institute on Aging/National Institutes of Health, Baltimore, MD 21224, USA.
authors.forename: Kevin G
authors.initials: KG
authors.lastname: Becker
authors.affiliation: Howard Hughes Medical Institute and Program in Systems Biology, Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA 01605-0103, USA.
authors.forename: Job
authors.initials: J
authors.lastname: Dekker
authors.affiliation: Department of Bioengineering, University of Illinois College of Engineering and College of Medicine, Chicago, IL 60612-7344, USA.
authors.forename: Jie
authors.initials: J
authors.lastname: Liang
authors.affiliation: Gene Regulation Section, Laboratory of Molecular Biology and Immunology, National Institute on Aging/National Institutes of Health, Baltimore, MD 21224, USA. Electronic address: senranja@grc.nia.nih.gov.
authors.forename: Ranjan
authors.initials: R
authors.lastname: Sen
authors.affiliation: Department of Microbiology and Immunology, University of Illinois College of Medicine, Chicago, IL 60612-7344, USA. Electronic address: star1@uic.edu.
authors.forename: Amy L
authors.initials: AL
authors.lastname: Kenter
mesh_terms: D000818:Animals; D000906:Antibodies / Q000235:genetics*; D001402:B-Lymphocytes / Q000378:metabolism*; D002460:Cell Line; D002478:Cells, Cultured; D002843:Chromatin / Q000737:chemistry / Q000235:genetics*; D042002:Chromatin Assembly and Disassembly; D056426:Genetic Loci; D051379:Mice; D008810:Mice, Inbred C57BL; D051757:PAX5 Transcription Factor / Q000378:metabolism
chemical_list: D000906:Antibodies; D002843:Chromatin; D051757:PAX5 Transcription Factor; C497282:Pax5 protein, mouse