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

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Abstract

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.

Original languageEnglish
Article number113074
Number of pages28
JournalCell Reports
Volume42
Issue number9
Early online date6 Sept 2023
DOIs
Publication statusPublished - 26 Sept 2023

Keywords

  • 3D immunoglobulin structure
  • Capture Hi-C
  • CP: Immunology
  • genome organization
  • immunoglobin locus
  • interchromosomal
  • polymer modeling

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