Intra- and interchromosomal contact mapping reveals the Igh locus has extensive conformational heterogeneity and interacts with B-lineage genes
Olga Mielczarek,
Carolyn H. Rogers,
Yinxiu Zhan,
Louise S. Matheson,
Michael J.T. Stubbington,
Stefan Schoenfelder,
Daniel J. Bolland,
Biola M. Javierre,
Steven W. Wingett,
Csilla Várnai,
Anne Segonds-Pichon,
Simon J. Conn,
Felix Krueger,
Simon Andrews,
Peter Fraser,
Luca Giorgetti,
Anne E. Corcoran
Affiliations
Olga Mielczarek
Nuclear Dynamics Programme, Babraham Institute, Babraham Research Campus, Cambridge CB22 3AT, UK
Carolyn H. Rogers
Nuclear Dynamics Programme, Babraham Institute, Babraham Research Campus, Cambridge CB22 3AT, UK; Immunology Programme, Babraham Institute, Babraham Research Campus, Cambridge CB22 3AT, UK
Yinxiu Zhan
Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, 4058 Basel, Switzerland
Louise S. Matheson
Nuclear Dynamics Programme, Babraham Institute, Babraham Research Campus, Cambridge CB22 3AT, UK; Immunology Programme, Babraham Institute, Babraham Research Campus, Cambridge CB22 3AT, UK
Michael J.T. Stubbington
Nuclear Dynamics Programme, Babraham Institute, Babraham Research Campus, Cambridge CB22 3AT, UK
Stefan Schoenfelder
Nuclear Dynamics Programme, Babraham Institute, Babraham Research Campus, Cambridge CB22 3AT, UK
Daniel J. Bolland
Nuclear Dynamics Programme, Babraham Institute, Babraham Research Campus, Cambridge CB22 3AT, UK; Immunology Programme, Babraham Institute, Babraham Research Campus, Cambridge CB22 3AT, UK
Biola M. Javierre
Nuclear Dynamics Programme, Babraham Institute, Babraham Research Campus, Cambridge CB22 3AT, UK
Steven W. Wingett
Bioinformatics Group, Babraham Institute, Babraham Research Campus, Cambridge CB22 3AT, UK
Csilla Várnai
Nuclear Dynamics Programme, Babraham Institute, Babraham Research Campus, Cambridge CB22 3AT, UK
Anne Segonds-Pichon
Bioinformatics Group, Babraham Institute, Babraham Research Campus, Cambridge CB22 3AT, UK
Simon J. Conn
Flinders Health and Medical Research Institute, College of Medicine and Public Health, Flinders University, Bedford Park, SA 5042, Australia
Felix Krueger
Bioinformatics Group, Babraham Institute, Babraham Research Campus, Cambridge CB22 3AT, UK
Simon Andrews
Bioinformatics Group, Babraham Institute, Babraham Research Campus, Cambridge CB22 3AT, UK
Peter Fraser
Nuclear Dynamics Programme, Babraham Institute, Babraham Research Campus, Cambridge CB22 3AT, UK
Luca Giorgetti
Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, 4058 Basel, Switzerland
Anne E. Corcoran
Nuclear Dynamics Programme, Babraham Institute, Babraham Research Campus, Cambridge CB22 3AT, UK; Immunology Programme, Babraham Institute, Babraham Research Campus, Cambridge CB22 3AT, UK; Corresponding author
Summary: To produce a diverse antibody repertoire, immunoglobulin heavy-chain (Igh) loci undergo large-scale alterations in structure to facilitate juxtaposition and recombination of spatially separated variable (VH), diversity (DH), and joining (JH) genes. These chromosomal alterations are poorly understood. Uncovering their patterns shows how chromosome dynamics underpins antibody diversity. Using tiled Capture Hi-C, we produce a comprehensive map of chromatin interactions throughout the 2.8-Mb Igh locus in progenitor B cells. We find that the Igh locus folds into semi-rigid subdomains and undergoes flexible looping of the VH genes to its 3′ end, reconciling two views of locus organization. Deconvolution of single Igh locus conformations using polymer simulations identifies thousands of different structures. This heterogeneity may underpin the diversity of V(D)J recombination events. All three immunoglobulin loci also participate in a highly specific, developmentally regulated network of interchromosomal interactions with genes encoding B cell-lineage factors. This suggests a model of interchromosomal coordination of B cell development.
