title: Multi-tiered Reorganization of the Genome during B Cell Affinity Maturation Anchored by a Germinal Center-Specific Locus Control Region.
abstract: During the humoral immune response, B cells undergo a dramatic change in phenotype to enable antibody affinity maturation in germinal centers (GCs). Using genome-wide chromosomal conformation capture (Hi-C), we found that GC B cells undergo massive reorganization of the genomic architecture that encodes the GC B cell transcriptome. Coordinate expression of genes that specify the GC B cell phenotype-most prominently BCL6-was achieved through a multilayered chromatin reorganization process involving (1) increased promoter connectivity, (2) formation of enhancer networks, (3) 5' to 3' gene looping, and (4) merging of gene neighborhoods that share active epigenetic marks. BCL6 was an anchor point for the formation of GC-specific gene and enhancer loops on chromosome 3. Deletion of a GC-specific, highly interactive locus control region upstream of Bcl6 abrogated GC formation in mice. Thus, large-scale and multi-tiered genomic three-dimensional reorganization is required for coordinate expression of phenotype-driving gene sets that determine the unique characteristics of GC B cells.
authors.affiliation: Division of Hematology and Medical Oncology, Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA; Department of Pharmacology, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Karen L
authors.initials: KL
authors.lastname: Bunting
authors.affiliation: Institute for Computational Biomedicine, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: T David
authors.initials: TD
authors.lastname: Soong
authors.affiliation: Division of Hematology and Medical Oncology, Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA; Department of Immunology and Microbial Pathogenesis, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Rajat
authors.initials: R
authors.lastname: Singh
authors.affiliation: Division of Hematology and Medical Oncology, Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA; Institute for Computational Biomedicine, Weill Cornell Medical College, New York, NY 10065, USA; Department of Physiology and Biophysics, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Yanwen
authors.initials: Y
authors.lastname: Jiang
authors.affiliation: Division of Hematology and Medical Oncology, Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Wendy
authors.initials: W
authors.lastname: Béguelin
authors.affiliation: Division of Hematology and Medical Oncology, Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: David W
authors.initials: DW
authors.lastname: Poloway
authors.affiliation: Division of Hematology and Medical Oncology, Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Brandon L
authors.initials: BL
authors.lastname: Swed
authors.affiliation: Division of Hematology and Medical Oncology, Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Katerina
authors.initials: K
authors.lastname: Hatzi
authors.affiliation: Department of Otorhinolaryngology, Weill Cornell Medical College/New York Presbyterian Hospital, New York, NY 10065, USA.
authors.forename: William
authors.initials: W
authors.lastname: Reisacher
authors.affiliation: Division of Hematology and Medical Oncology, Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA; Institute for Computational Biomedicine, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Matt
authors.initials: M
authors.lastname: Teater
authors.affiliation: Institute for Computational Biomedicine, Weill Cornell Medical College, New York, NY 10065, USA. Electronic address: ole2001@med.cornell.edu.
authors.forename: Olivier
authors.initials: O
authors.lastname: Elemento
authors.affiliation: Division of Hematology and Medical Oncology, Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA; Department of Pharmacology, Weill Cornell Medical College, New York, NY 10065, USA. Electronic address: amm2014@med.cornell.edu.
authors.forename: Ari M
authors.initials: AM
authors.lastname: Melnick
mesh_terms: D000818:Animals; D000915:Antibody Affinity / Q000276:immunology*; D000917:Antibody Formation / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology*; D002893:Chromosomes, Human, Pair 3 / Q000276:immunology; D044127:Epigenesis, Genetic / Q000276:immunology; D016678:Genome / Q000276:immunology*; D018858:Germinal Center / Q000276:immunology*; D006801:Humans; D056724:Immunity, Humoral / Q000276:immunology; D019901:Locus Control Region / Q000276:immunology*; D051379:Mice; D011401:Promoter Regions, Genetic / Q000276:immunology; D051560:Proto-Oncogene Proteins c-bcl-6 / Q000276:immunology
chemical_list: D051560:Proto-Oncogene Proteins c-bcl-6