Since the mid-1990s, sphingosine-1-phosphate (S1P) has become one of the most widely studied lipid mediators. Many of the biological effects of S1P are mediated by signalling through cell surface receptors but researchers led by a team at Virginia Commonwealth University School of Medicine have now discovered a new role for this versatile lipid. Writing in the September 4th issue of the journal Science, they report that S1P is also produced in the cell nucleus by type 2 sphingosine kinase and plays an important role in gene regulation by inhibiting histone deacetylases (HDACs). Histones are the main protein component of chromatin and play a role in gene regulation, a function which is further refined by post-translational modifications. Acetylation of positively charged amino groups on the histone by histone acetyltransferase enzymes reduces its ability to bind to negatively charged phosphate residues on DNA and allows gene transcription to take place. HDACs are a family of enzymes that remove these acetyl groups, increasing binding to DNA and preventing transcription. The use of synthetic HDAC inhibitors as chemotherapeutic agents to treat a variety of cancers is being explored but physiological regulators of HDACs had not previously been identified. The new study shows that S1P is an important endogenous epigenetic regulator of gene expression and may help in the design of new HDAC inhibitors.