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Journal article
Locus folding mechanisms determine modes of antigen receptor gene assembly
The Journal of experimental medicine, v 221(2)
05 Feb 2024
PMID: 38189780
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
The dynamic folding of genomes regulates numerous biological processes, including antigen receptor (AgR) gene assembly. We show that, unlike other AgR loci, homotypic chromatin interactions and bidirectional chromosome looping both contribute to structuring Tcrb for efficient long-range V(D)J recombination. Inactivation of the CTCF binding element (CBE) or promoter at the most 5'Vβ segment (Trbv1) impaired loop extrusion originating locally and extending to DβJβ CBEs at the opposite end of Tcrb. Promoter or CBE mutation nearly eliminated Trbv1 contacts and decreased RAG endonuclease-mediated Trbv1 recombination. Importantly, Trbv1 rearrangement can proceed independent of substrate orientation, ruling out scanning by DβJβ-bound RAG as the sole mechanism of Vβ recombination, distinguishing it from Igh. Our data indicate that CBE-dependent generation of loops cooperates with promoter-mediated activation of chromatin to juxtapose Vβ and DβJβ segments for recombination through diffusion-based synapsis. Thus, the mechanisms that fold a genomic region can influence molecular processes occurring in that space, which may include recombination, repair, and transcriptional programming.
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Details
- Title
- Locus folding mechanisms determine modes of antigen receptor gene assembly
- Creators
- Brittney M Allyn - University of PennsylvaniaKatharina E Hayer - Raymond and Ruth Perelman School of Medicine at the University of PennsylvaniaClement Oyeniran - The Ohio State UniversityVincent Nganga - The Ohio State UniversityKyutae Lee - University of PennsylvaniaBikash Mishra - The Ohio State UniversityAhmet Sacan - Biomedical Engineering Doctoral Degree Program, School of Biomedical Engineering, Science and Health Systems, Drexel University , Philadelphia, PA, USAEugene M Oltz - The Ohio State UniversityCraig H Bassing - University of Pennsylvania
- Publication Details
- The Journal of experimental medicine, v 221(2)
- Publisher
- Rockefeller University Press
- Grant note
- R01 AI130231 / NIH HHS
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- School of Biomedical Engineering, Science, and Health Systems
- Web of Science ID
- WOS:001138388700001
- Scopus ID
- 2-s2.0-85182024482
- Other Identifier
- 991021818477604721
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- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Immunology
- Medicine, Research & Experimental