Enhancers of the PAIR4 regulatory module promote distal VH gene recombination at the Igh locus. 2023

Louisa Hill, and Markus Jaritz, and Hiromi Tagoh, and Karina Schindler, and Daniela Kostanova-Poliakova, and Qiong Sun, and Tanja A Schwickert, and Martin Leeb, and Meinrad Busslinger
Research Institute of Molecular Pathology (IMP), Vienna BioCenter (VBC), Vienna, Austria.

While extended loop extrusion across the entire Igh locus controls VH -DJH recombination, local regulatory sequences, such as the PAIR elements, may also activate VH gene recombination in pro-B-cells. Here, we show that PAIR-associated VH 8 genes contain a conserved putative regulatory element (V8E) in their downstream sequences. To investigate the function of PAIR4 and its V8.7E, we deleted 890 kb containing all 14 PAIRs in the Igh 5' region, which reduced distal VH gene recombination over a 100-kb distance on either side of the deletion. Reconstitution by insertion of PAIR4-V8.7E strongly activated distal VH gene recombination. PAIR4 alone resulted in lower induction of recombination, indicating that PAIR4 and V8.7E function as one regulatory unit. The pro-B-cell-specific activity of PAIR4 depends on CTCF, as mutation of its CTCF-binding site led to sustained PAIR4 activity in pre-B and immature B-cells and to PAIR4 activation in T-cells. Notably, insertion of V8.8E was sufficient to activate VH gene recombination. Hence, enhancers of the PAIR4-V8.7E module and V8.8E element activate distal VH gene recombination and thus contribute to the diversification of the BCR repertoire in the context of loop extrusion.

UI MeSH Term Description Entries
D011995 Recombination, Genetic Production of new arrangements of DNA by various mechanisms such as assortment and segregation, CROSSING OVER; GENE CONVERSION; GENETIC TRANSFORMATION; GENETIC CONJUGATION; GENETIC TRANSDUCTION; or mixed infection of viruses. Genetic Recombination,Recombination,Genetic Recombinations,Recombinations,Recombinations, Genetic
D012045 Regulatory Sequences, Nucleic Acid Nucleic acid sequences involved in regulating the expression of genes. Nucleic Acid Regulatory Sequences,Regulatory Regions, Nucleic Acid (Genetics),Region, Regulatory,Regions, Regulatory,Regulator Regions, Nucleic Acid,Regulatory Region,Regulatory Regions
D001665 Binding Sites The parts of a macromolecule that directly participate in its specific combination with another molecule. Combining Site,Binding Site,Combining Sites,Site, Binding,Site, Combining,Sites, Binding,Sites, Combining
D054448 Precursor Cells, B-Lymphoid Lymphocyte progenitor cells that are restricted in their differentiation potential to the B lymphocyte lineage. The pro-B cell stage of B lymphocyte development precedes the pre-B cell stage. B-Lymphoid Precursor Cell,Immature B Cell,Immature B-Cell,Immature B-Lymphocyte,Immature B-Lymphocytes,Pre-B Cell,Pre-B Lymphocyte,Pre-B Lymphocytes,Pre-B-Cell,Precursor B-Cell,Precursor B-Lymphocyte,Precursor B-Lymphocytes,Pro-B Cell,Pro-B Lymphocyte,Pro-B-Cell,Progenitor B-Cell,Progenitor B-Lymphocyte,Progenitor B-Lymphocytes,Transitional B-Cell,Transitional B-Lymphocyte,Transitional B-Lymphocytes,B-Lymphoid Precursor Cells,Immature B-Cells,Pre-B Cells,Pre-B-Cells,Precursor B-Cells,Pro-B Cells,Pro-B Lymphocytes,Pro-B-Cells,Progenitor B-Cells,Transitional B-Cells,B Cell, Immature,B Cells, Immature,B Lymphoid Precursor Cell,B Lymphoid Precursor Cells,B-Cell, Immature,B-Cell, Precursor,B-Cell, Progenitor,B-Cell, Transitional,B-Cells, Immature,B-Cells, Precursor,B-Cells, Progenitor,B-Cells, Transitional,B-Lymphocyte, Immature,B-Lymphocyte, Precursor,B-Lymphocyte, Progenitor,B-Lymphocyte, Transitional,B-Lymphocytes, Immature,B-Lymphocytes, Precursor,B-Lymphocytes, Progenitor,B-Lymphocytes, Transitional,Cell, B-Lymphoid Precursor,Cell, Immature B,Cell, Pre-B,Cell, Pro-B,Cells, B-Lymphoid Precursor,Cells, Immature B,Cells, Pre-B,Cells, Pro-B,Immature B Cells,Immature B Lymphocyte,Immature B Lymphocytes,Lymphocyte, Pre-B,Lymphocyte, Pro-B,Lymphocytes, Pre-B,Lymphocytes, Pro-B,Pre B Cell,Pre B Cells,Pre B Lymphocyte,Pre B Lymphocytes,Precursor B Cell,Precursor B Cells,Precursor B Lymphocyte,Precursor B Lymphocytes,Precursor Cell, B-Lymphoid,Precursor Cells, B Lymphoid,Pro B Cell,Pro B Cells,Pro B Lymphocyte,Pro B Lymphocytes,Progenitor B Cell,Progenitor B Cells,Progenitor B Lymphocyte,Progenitor B Lymphocytes,Transitional B Cell,Transitional B Cells,Transitional B Lymphocyte,Transitional B Lymphocytes

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