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标题：Deacetylase activity of histone deacetylase 3 is required for productive VDJ recombination and B-cell development
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作者：Kristy R. Stengel ; Kelly R. Barnett ; Jing Wang 等
期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2017
卷号：114
期号：32
页码：8608-8613
DOI：10.1073/pnas.1701610114
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Histone deacetylase 3 (HDAC3) is the catalytic component of NCoR/SMRT corepressor complexes that mediate the actions of transcription factors implicated in the regulation of B-cell development and function. We crossed Hdac3 conditional knockout mice with Mb1-Cre knockin animals to delete Hdac3 in early progenitor B cells. The spleens of Hdac3 ^F/− Mb1-Cre ^+/− mice were virtually devoid of mature B cells, and B220⁺CD43⁺ B-cell progenitors accumulated within the bone marrow. Quantitative deep sequencing of the Ig heavy chain locus from B220⁺CD43⁺ populations identified a defect in V _H DJ _H recombination with a severe reduction in productive rearrangements, which directly corresponded to the loss of pre-B cells from Hdac3 ^{Δ /−} bone marrow. For Hdac3 ^{Δ /−} B cells that did show productive VDJ rearrangement, there was significant skewing toward the incorporation of proximal V _H gene segments and a corresponding reduction in distal V _H gene segment use. Although transcriptional effects within these loci were modest, Hdac3 ^{Δ /−} progenitor cells displayed global changes in chromatin structure that likely hindered effective distal V-DJ recombination. Reintroduction of wild-type Hdac3 restored normal B-cell development, whereas an Hdac3 point mutant lacking deacetylase activity failed to complement this defect. Thus, the deacetylase activity of Hdac3 is required for the generation of mature B cells.
关键词：histone deacetylase ; chromatin structure ; B-cell development ; HDAC3 ; VDJ recombination