We have found rapid induction of various genes, including human globin genes, in response to hexamethylene bisacetamide (HMBA) and dimethyl sulfoxide (DMSO) in transiently transfected cells. In mouse erythroleukemia cells (MELCs), this effect is detected within 1 hr of exposure of the cells to inducer before the endogenous mouse globin genes are induced. It does not require protein synthesis and is reversed if the inducer is removed. This and other evidence suggest that the mechanism involves a change in activity of a factor intimately involved with transcription, probably as a result of post-translational modification. As such, it may represent an early triggering event in terminal differentiation, and its relevance to the expression of human globin genes in stable transfectants and to induction of the mouse globin genes is discussed. Other cell lines (K562 and NSO) also show this response, which may therefore involve a ubiquitous mechanism. We also found that HMBA depresses the expression of endogenous globin genes in K562, the opposite of this differentiation inducer's effect on MELC.