Intra- and interchromosomal contact mapping reveals the Igh locus has extensive conformational heterogeneity and interacts with B-lineage genes
Year: 2023
Type: article
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 (V H ), diversity (D H ), and joining (J H ) 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 V H 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.
Source: Cell Reports
Authors: 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
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $5,460
Funders: National Science Foundation, Novartis Foundation, Babraham Institute, European Commission, Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung, Directorate for Biological Sciences, Horizon 2020 Framework Programme, Medical Research Council, Biotechnology and Biological Sciences Research Council, European Research Council, National Health and Medical Research Council, Horizon 2020, H2020 European Research Council, H2020 Marie Skłodowska-Curie Actions
Awards: G1990583613, Predictive Epigenetics: Fusing Theory and Experiment, Computational systems biology of ageing in haematopoiesis and the immune system, Genomic and epigenomic analysis of ageing in haematopoiesis and the immune system., Circular RNAs as genome destabilisers in human disease, G3023828317, G3545243325, G355637961, Predictive Epigenetics: Fusing Theory and Experiment, G434337789, Chromatin architecture and Design, Chromosome structure and transcriptional regulation in single living cells, Develop a mechanistic understanding of how transcriptional and posttranscriptional regulation of gene expression is coordinated by signal transduction pathways., Chromatin architecture and Design, G6160911136, Immune homeostasis and the immune response, G7887713238, G8690818240, G8755156122, Biophysical mechanisms of long-range transcriptional regulation
OpenAlex ID: W4386478924