COORDINATION OF PROTEIN-DNA INTERACTIONS IN THE PROMOTERS OF HUMAN H4, H3, AND H1 HISTONE GENES DURING THE CELL-CYCLE, TUMORIGENESIS, AND DEVELOPMENT

Coordinate transcriptional control of replication-dependent human H4, H3, and H1 histone genes was studied by comparing levels of H3 and H1 histone promoter binding activities with those of H4 histone promoter factor HiNF-D during the cell cycle of both normal diploid and tumor-derived cells, as well as in fetal and adult mammalian tissues. Both H3 and H1 histone promoters interact with binding activities that, as with HiNF-D, are maximal during S-phase but at low levels in the G1-phase of normal diploid cells. However, these analogous DNA binding activities are constitutively maintained at high levels throughout the cell cycle in four different transformed and tumor-derived cells. Downregulation of the H3 and H1 histone promoter factors in conjunction with HiNF-D is observed in vivo at the onset of quiescence and differentiation during hepatic development. Hence, our results indicate a tight temporal coupling of three separate protein-DNA interactions in different histone promoters during the cell cycle, development, and tumorigenesis. This suggests that a key oscillatory, cell-growth-control mechanism modulates three analogous histone gene promoter protein-DNA interactions in concert. The derangement of this mechanism in four distinct tumor cells implies that concerted deregulation of these histone promoter factors is a common event resulting from heterogeneous aberrations in normal cell growth mechanisms during tumorigenesis. We postulate that this mechanism may be involved in the coordinate regulation of the human H4, H3, and H1 histone multigene families.