The coding sequences of mouse H2A and H3 histone genes contains a conserved seven nucleotide element that interacts with nuclear factors and is necessary for normal expression.

Expression of replication-dependent histone genes of all classes is up-regulated coordinately at the onset of DNA synthesis. The cellular signals involved in coordinate regulation of these genes are not known. Here we report identification of an alpha element, present within the mouse histone coding region activating sequence (CRAS). We show evidence that this element is present in histone genes from two classes, H2a and H3, in the mouse. This element has two biological functions in histone gene expression, i.e. the element interacts with nuclear proteins in regulation of gene expression, as well as encoding the amino acids of the histone proteins. We present both in vivo and in vitro evidence that interaction of nuclear proteins with this element is required for normal expression. The binding site for nuclear protein(s) has been precisely defined by means of synthetic oligonucleotides, as well as DNase I protection and methylation interference. It is interesting to note that the histone CRAS alpha element is mutated in a replication-independent H3.3 gene; 5 of 7 nt in the CRAS alpha box are changed in this gene.