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

Kristy R. Stengel, Kelly R. Barnett, Jing Wang, Qi Liu, Emily Hodges, Scott W. Hiebert, Srividya Bhaskara

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

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 Hdac3F/−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 Hdac3Δ/ bone marrow. For Hdac3Δ/ 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, Hdac3Δ/ 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.

Original languageEnglish (US)
Pages (from-to)8608-8613
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume114
Issue number32
DOIs
StatePublished - Aug 8 2017
Externally publishedYes

Keywords

  • B-cell development
  • Chromatin structure
  • HDAC3
  • Histone deacetylase
  • VDJ recombination

ASJC Scopus subject areas

  • General

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