Regulated expression of mammalian histone H4 genes in vivo requires a trans-acting transcription factor

Mouse L cells containing integrated copies of a human histone H4 gene have been obtained by cotransfection with the herpesvirus thymidine kinase gene. Nuclease S1 assays of RNA from several independent cell lines show that the expression of the introduced H4 gene is regulated during the cell cycle. One of these cell lines (line 6-8) contains more than 60 human H4 gene copies per haploid genome and does not express the endogenous mouse histone H4 mRNA. In contrast, the expression of the mouse H2a and H3 mRNAs in this cell line is not perturbed. In cell revertants that have lost the majority of the human H4 gene copies, the expression of the mouse H4 mRNA is restored, demonstrating that the mouse genes remain functional although not expressed. The rate of transcription of the histone H4 genes in clone 6-8 is at least 10-fold greater than that of the parental cell line and it is regulated during traversal of the cell cycle. These results show that the expression of mammalian histone H4 genes involves both a trans-acting transcriptional regulatory factor and an H4-specific activity. We propose that cell cycle regulation of histone gene expression may be effected through subtype-specific transcriptional regulatory proteins.