Histone genes are expressed during the S phase of the cell cycle. Control is at multiple levels and is mediated by the integration of regulatory signals in response to cell-cycle progression and the onset of differentiation. Much work has been carried out on the H4 gene promoter, which appears to be organized into a series of distinct regulatory elements. The three-dimensional organization of the promoter and, in particular, its spatial relationship with the nuclear matrix scaffold, may be important factors of transcription regulation.