The study investigates the role of sphingosine-1-phosphate (S1P) in regulating histone acetylation within the nucleus. Sphingosine kinase 2 (SphK2), one of the enzymes that produces S1P, was found to associate with histone H3 and produce S1P, which specifically binds to and inhibits histone deacetylases HDAC1 and HDAC2. This inhibition prevents the removal of acetyl groups from lysine residues in histone tails, leading to increased histone acetylation. SphK2 was also found to be enriched at the promoters of genes encoding the cyclin-dependent kinase inhibitor p21 and the transcriptional regulator c-fos, where it enhanced local histone H3 acetylation and transcription. The study concludes that HDACs are direct intracellular targets of S1P, linking nuclear S1P to epigenetic regulation of gene expression.The study investigates the role of sphingosine-1-phosphate (S1P) in regulating histone acetylation within the nucleus. Sphingosine kinase 2 (SphK2), one of the enzymes that produces S1P, was found to associate with histone H3 and produce S1P, which specifically binds to and inhibits histone deacetylases HDAC1 and HDAC2. This inhibition prevents the removal of acetyl groups from lysine residues in histone tails, leading to increased histone acetylation. SphK2 was also found to be enriched at the promoters of genes encoding the cyclin-dependent kinase inhibitor p21 and the transcriptional regulator c-fos, where it enhanced local histone H3 acetylation and transcription. The study concludes that HDACs are direct intracellular targets of S1P, linking nuclear S1P to epigenetic regulation of gene expression.