We have isolated a variant human H2B core (GL105) histone gene and a variant Hl linker (CI110) histone cDNA. The H2B histone gene expresses alternative mRNAs regulated differentially during the HeLa cell cycle.. The H2B gene encodes both a 500 nt replication-dependent mRNA and a 2300 NT HHC89 constitutively expressed mRNA. The 3' end of the cell cycle regulated mRNA terminates immediately following the region of hyphenated dyad symmetry typical of most histone mRNAs, whereas the constitutively expressed HHC289 mRNA has a 1798 nt non-translated trailer that contains the same region of hyphenated dyad symmetry but is polyadenylated. Our results demonstrate that replication-dependent and constitutively expressed histone mRNAs can be encoded by the same gene and indicate that alternative 3' end processing is a major level of regulation by which cells can modulate the synthesis of variant histone proteins during the cell cycle and at the onset of differentiation. When Northern blot analysis was carried out we observed the 2300 nt expression of a second variant H2B gene. The H1 histone gene, like the H2B variant, contains a 3' region of hyphenated dyad symmetry and a polyaddenylation sequence. The regulation of this gene is now under investigation. The long-range objective of these studies is to understand the cellular mechanisms and signals, that modulate the expression and processing of RNA transcripts from the variant histone genes under different biological conditions. These studies will address the extent to which the expression of variant histone genes is modulated by the growth state of the cell. We will also examine the role specific nucleotide sequences play in the regulation and alternative processing of variant human histone mRNAs. The post-transcriptional regulation of variant human histone genes will be analyzed during changes in the proliferative state of the cell. These results will provide additional insight into eukaryotic gene expression growth regulation, differentiation, and carcinogenesis.