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Hodges Lab

Deacetylase activity of histone deacetylase 3 is required for productive VDJ recombination and B-cell development.

AUTHORS

Stengel KRKristy R , Barnett KR Kelly R , Wang J Jing , Liu Q Qi , Hodges E Emily , Hiebert SW Scott W , Bhaskara S Srividya . Proceedings of the National Academy of Sciences of the United States of America. 2017 7 24; ().

ABSTRACT

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 VHDJH 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 VH gene segments and a corresponding reduction in distal VH 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.