Item Type: | Article |
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Title: | Orientation regulation of class-switch recombination in human B cells |
Creators Name: | Du, L., Oksenych, V., Wan, H., Ye, X., Dong, J., Ye, A.Y., Abolhassani, H., Vlachiotis, S., Zhang, X., de la Rosa, K., Hammarström, L., van der Burg, M., Alt, F.W. and Pan-Hammarström, Q. |
Abstract: | We developed a linear amplification-mediated high-throughput genome-wide translocation sequencing method to profile Ig class-switch recombination (CSR) in human B cells in an unbiased and quantitative manner. This enables us to characterize CSR junctions resulting from either deletional recombination or inversion for each Ig class/subclass. Our data showed that more than 90% of CSR junctions detected in peripheral blood in healthy control subjects were due to deletional recombination. We further identified two major CSR junction signatures/patterns in human B cells. Signature 1 consists of recombination junctions resulting from both IgG and IgA switching, with a dominance of Sµ-Sγ junctions (72%) and deletional recombination (87%). Signature 2 is contributed mainly by Sµ-Sα junctions (96%), and these junctions were almost all due to deletional recombination (99%) and were characterized by longer microhomologies. CSR junctions identified in healthy individuals can be assigned to both signatures but with a dominance of signature 1, whereas almost all CSR junctions found in patients with defects in DNA-PKcs or Artemis, two classical nonhomologous end joining (c-NHEJ) factors, align with signature 2. Thus, signature 1 may represent c-NHEJ activity during CSR, whereas signature 2 is associated with microhomology-mediated alternative end joining in the absence of the studied c-NHEJ factors. Our findings suggest that in human B cells, the efficiency of the c-NHEJ machinery and the features of switch regions are crucial for the regulation of CSR orientation. Finally, our high-throughput method can also be applied to study the mechanism of rare types of recombination, such as switching to IgD and locus suicide switching. |
Source: | Journal of Immunology |
ISSN: | 0022-1767 |
Publisher: | American Association of Immunologists |
Date: | 9 September 2024 |
Official Publication: | https://doi.org/10.4049/jimmunol.2300842 |
PubMed: | View item in PubMed |
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