Multi-tiered Reorganization of the Genome during B Cell Affinity Maturation Anchored by a Germinal Center-Specific Locus Control Region.

TitleMulti-tiered Reorganization of the Genome during B Cell Affinity Maturation Anchored by a Germinal Center-Specific Locus Control Region.
Publication TypeJournal Article
Year of Publication2016
AuthorsBunting KL, T Soong D, Singh R, Jiang Y, B├ęguelin W, Poloway DW, Swed BL, Hatzi K, Reisacher W, Teater M, Elemento O, Melnick AM
JournalImmunity
Volume45
Issue3
Pagination497-512
Date Published2016 09 20
ISSN1097-4180
KeywordsAnimals, Antibody Affinity, Antibody Formation, B-Lymphocytes, Chromosomes, Human, Pair 3, Epigenesis, Genetic, Genome, Germinal Center, Humans, Immunity, Humoral, Locus Control Region, Mice, Promoter Regions, Genetic, Proto-Oncogene Proteins c-bcl-6
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.

DOI10.1016/j.immuni.2016.08.012
Alternate JournalImmunity
PubMed ID27637145
PubMed Central IDPMC5033726
Grant ListP30 DK020541 / DK / NIDDK NIH HHS / United States
R01 CA104348 / CA / NCI NIH HHS / United States
R01 CA187109 / CA / NCI NIH HHS / United States
R01 CA194547 / CA / NCI NIH HHS / United States