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

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 V_HDJ_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.

Keywords: B-cell development; HDAC3; VDJ recombination; chromatin structure; histone deacetylase.