Igh and Igk loci use different folding principles for V gene recombination due to distinct chromosomal architectures of pro-B and pre-B cells

Louisa Hill, Gordana Wutz, Markus Jaritz, Hiromi Tagoh, Lesly Calderón, Jan-Michael Peters, Anton Goloborodko and Meinrad Busslinger ()
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Louisa Hill: Vienna BioCenter (VBC)
Gordana Wutz: Vienna BioCenter (VBC)
Markus Jaritz: Vienna BioCenter (VBC)
Hiromi Tagoh: Vienna BioCenter (VBC)
Lesly Calderón: Vienna BioCenter (VBC)
Jan-Michael Peters: Vienna BioCenter (VBC)
Anton Goloborodko: Austrian Academy of Sciences, Vienna BioCenter (VBC)
Meinrad Busslinger: Vienna BioCenter (VBC)

Nature Communications, 2023, vol. 14, issue 1, 1-16

Abstract: Abstract Extended loop extrusion across the immunoglobulin heavy-chain (Igh) locus facilitates VH-DJH recombination following downregulation of the cohesin-release factor Wapl by Pax5, resulting in global changes in the chromosomal architecture of pro-B cells. Here, we demonstrate that chromatin looping and VK-JK recombination at the Igk locus were insensitive to Wapl upregulation in pre-B cells. Notably, the Wapl protein was expressed at a 2.2-fold higher level in pre-B cells compared with pro-B cells, which resulted in a distinct chromosomal architecture with normal loop sizes in pre-B cells. High-resolution chromosomal contact analysis of the Igk locus identified multiple internal loops, which likely juxtapose VK and JK elements to facilitate VK-JK recombination. The higher Wapl expression in Igμ-transgenic pre-B cells prevented extended loop extrusion at the Igh locus, leading to recombination of only the 6 most 3’ proximal VH genes and likely to allelic exclusion of all other VH genes in pre-B cells. These results suggest that pro-B and pre-B cells with their distinct chromosomal architectures use different chromatin folding principles for V gene recombination, thereby enabling allelic exclusion at the Igh locus, when the Igk locus is recombined.

Date: 2023
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DOI: 10.1038/s41467-023-37994-9

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