Histone deacetylases (HDACs) are enzymes that remove the acetyl groups from acetylated lysine residues of histones. The reaction produces a positively charged, unmodified lysine residue that enables the histone to interact more tightly with negatively charged DNA. In general, this promotes packaging of DNA into chromatin, thereby suppressing its replication, transcription, or repair. HDAC3 serves this function as part of the corepressor complex NCoR/SMRT, which is known to play an important role in heterochromatin maintenance in some cells and tissues. Among these HDAC3-dependent cells, as discovered by Vanderbilt Basic Sciences investigator Scott Hiebert, his laboratory, and his collaborator Srividya Bhaskara (University of Utah), are the B cells of the immune system. This discovery resulted from studies using genetically engineered mice in which HDAC3 expression was selectively deleted in developing B cells. A key step in early B cell differentiation is the splicing together of three segments in the gene for the immunoglobulin heavy chain, a process known as VDJ recombination. The resultant heavy chain gene is then expressed as part of a B cell receptor, which serves as a key signaling molecule to spur further differentiation. In the absence of HDAC3, however, heavy chain gene recombination did not occur, and a stark absence of mature B cells in the mutant mice resulted. The investigators found that recombinations involving gene segments that were far apart on the chromosome were the most likely to be blocked by the HDAC3 deficiency. Reintroduction of wild-type HDAC3 into the deficient mice restored B-cell development, but this was not the case for reintroduction of a catalytically inactive mutant HDAC3. The findings demonstrate that HDAC3 is a key component in B cell development through its regulation of gene recombination and that HDAC3 catalytic activity is required for it to execute this function. The work is published in the journal Proceedings of the National Academy of Sciences USA [K.R. Stengel, et al., (2017) Proc. Natl. Acad. Sci. USA, published online July 24, DOI: 10.1073/pnas.1701610114].