(Nuclear Dynamics Programme. Babraham Institute. Babraham Research Campus)
(Immunology Programme. Babraham Institute. Babraham Research Campus)
(Immunology Programme. Babraham Institute. Babraham Research Campus)
(Nuclear Dynamics Programme. Babraham Institute. Babraham Research Campus)
(Nuclear Dynamics Programme. Babraham Institute. Babraham Research Campus)
| Data: |
2023 |
| Resum: |
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), diversity (D), and joining (J) 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 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. |
| Ajuts: |
European Commission 759366
|
| Nota: |
We thank Philipp Voigt for critical reading of the manuscript; Hashem Koohy, Jonathan Cairns, Peter Chovanec, and Bhupinder Virk for assistance with bioinformatics; Kristina Tabbada for assistance with sequencing; and Simon Walker for assistance with microscopy. We are grateful to Rudi Hendriks, Erasmus MC, Rotterdam for providing the Rag81X mouse strain. O.M. (1426107) and C.R. (1947339) were supported by PhD studentships from the Medical Research Council, UK. S.J.C. was supported by an Investigator Grant (Leadership, GNT1198014) awarded by the National Health and Medical Research Council (NHMRC). Research in L.G.'s lab was funded by the Novartis Foundation, the European Research Council (grant no. 759366, BioMeTre), Marie Skłodowska-Curie Innovative Training Networks (grant nos. 813327 ChromDesign and 813282 PEP-NET) under the European Union's Horizon 2020 Research and Innovation Program, and the Swiss National Science Foundation (grant no. 310030_192642). Research in A.E.C.'s laboratory was supported by grants from the Biotechnology and Biological Sciences Research Council (BBS/E/B/000C0404, BBS/E/B/000C0405, BBS/E/B/000C0427, BBS/E/B/000C0428). The Babraham Institute provides funds, through the BBSRC, for open access publication fees. |
| Nota: |
We thank Philipp Voigt for critical reading of the manuscript; Hashem Koohy, Jonathan Cairns, Peter Chovanec, and Bhupinder Virk for assistance with bioinformatics; Kristina Tabbada for assistance with sequencing; and Simon Walker for assistance with microscopy. We are grateful to Rudi Hendriks, Erasmus MC, Rotterdam for providing the Rag81X mouse strain. O.M. (1426107) and C.R. (1947339) were supported by PhD studentships from the Medical Research Council, UK. S.J.C. was supported by an Investigator Grant (Leadership, GNT1198014) awarded by the National Health and Medical Research Council (NHMRC). Research in L.G.'s lab was funded by the Novartis Foundation, the European Research Council (grant no. 759366, BioMeTre), Marie Skłodowska-Curie Innovative Training Networks (grant nos. 813327 ChromDesign and 813282 PEP-NET) under the European Union's Horizon 2020 Research and Innovation Program, and the Swiss National Science Foundation (grant no. 310030_192642). Research in A.E.C.'s laboratory was supported by grants from the Biotechnology and Biological Sciences Research Council (BBS/E/B/000C0404, BBS/E/B/000C0405, BBS/E/B/000C0427, BBS/E/B/000C0428). The Babraham Institute provides funds, through the BBSRC, for open access publication fees. M.J.T.S. S.S. S.J.C. and A.E.C. conceptualized the study. S.S. M.J.T.S. and D.J.B. devised the method. O.M. C.H.R. L.S.M. B.M.J. M.J.T.S. and D.J.B. performed experiments. Y.Z. performed modeling. O.M. C.H.R. Y.Z. L.S.M. S.W.W. A.S.-P. F.K. S.A. and C.V. analyzed data. P.F. L.G. and A.E.C. secured funding and supervised research. O.M. C.H.R. L.S.M. and A.E.C. wrote the manuscript with input from all other authors. P.F. and S.S. are co-founders and shareholders of Enhanc3D Genomics Ltd. We worked to ensure sex balance in the selection of non-human subjects. We worked to ensure diversity in experimental samples through the selection of the genomic datasets. While citing references scientifically relevant for this work, we also actively worked to promote gender balance in our reference list. We support inclusive, diverse, and equitable conduct of research. |
| Drets: |
Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.  |
| Llengua: |
Anglès |
| Document: |
Article ; recerca ; Versió publicada |
| Matèria: |
Immunoglobin locus ;
Capture Hi-C ;
Polymer modeling ;
3D immunoglobulin structure ;
Genome organization ;
Interchromosomal |
| Publicat a: |
Cell reports, Vol. 42 Núm. 9 (26 2023) , p. 113074, ISSN 2211-1247 |
visitant ::
identificació
(Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
