A histone modification thought by many to be a crude bulldozer can contribute to the fine molding of cell behavior, according to a study on page 1825. Rossig et al. show that histone deacetylase (HDAC) activity is required for adult progenitor cells to commit to the endothelial cell lineage. In these cells, HDAC activity was specifically required for the induction of the transcription factor HoxA9, which may be a master regulator of endothelial cell commitment.

HoxA9 was able to drive cell differentiation due to its ability to activate the expression of endothelial cell–specific genes, including endothelial cell nitric oxide synthase (eNOS). In addition, HoxA9-deficient mice were unable to recover from ischemic injury, a process that requires formation of new endothelial cells from circulating progenitors.

But the involvement of HDACs in this process may seem counterintuitive, as histone deacetylation of gene promoter elements is normally associated with transcriptional silencing. Indeed, recent reports showed that eNOS expression itself is suppressed by HDAC activity in nonendothelial cells.

The protein complex responsible for activating HoxA9 expression was, however, recently shown to contain HDAC proteins. HDACs can modify nonhistone proteins, including transcription factors, and the acetylation or deacetylation state of these factors can influence target gene activation. The authors suspect that modification of nonhistone proteins may govern the induction of HoxA9.