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Publication : Lsh/HELLS is required for B lymphocyte development and immunoglobulin class switch recombination.

First Author  He Y Year  2020
Journal  Proc Natl Acad Sci U S A Volume  117
Issue  33 Pages  20100-20108
PubMed ID  32727902 Mgi Jnum  J:293808
Mgi Id  MGI:6451886 Doi  10.1073/pnas.2004112117
Citation  He Y, et al. (2020) Lsh/HELLS is required for B lymphocyte development and immunoglobulin class switch recombination. Proc Natl Acad Sci U S A 117(33):20100-20108
abstractText  Mutation of HELLS (Helicase, Lymphoid-Specific)/Lsh in human DNA causes a severe immunodeficiency syndrome, but the nature of the defect remains unknown. We assessed here the role of Lsh in hematopoiesis using conditional Lsh knockout mice with expression of Mx1 or Vav Cre-recombinase. Bone marrow transplantation studies revealed that Lsh depletion in hematopoietic stem cells severely reduced B cell numbers and impaired B cell development in a hematopoietic cell-autonomous manner. Lsh-deficient mice without bone marrow transplantation exhibited lower Ig levels in vivo compared to controls despite normal peripheral B cell numbers. Purified B lymphocytes proliferated normally but produced less immunoglobulins in response to in vitro stimulation, indicating a reduced capacity to undergo class switch recombination (CSR). Analysis of germline transcripts, examination of double-stranded breaks using biotin-labeling DNA break assay, and End-seq analysis indicated that the initiation of the recombination process was unscathed. In contrast, digestion-circularization PCR analysis and high-throughput sequencing analyses of CSR junctions and a chromosomal break repair assay indicated an impaired ability of the canonical end-joining pathway in Lsh-deficient B cells. Our data suggest a hematopoietic cell-intrinsic role of Lsh in B cell development and in CSR providing a potential target for immunodeficiency therapy.
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