Multiple Mechanisms Regulate the Proliferation-Specific Histone Gene Transcription Factor HiNF-D in Normal Human Diploid Fibroblasts

Kenneth L. Wright, Andre J. van Wijnen, Janet L. Stein, Gary S. Stein, Robert T. Dell'Orco

Research output: Contribution to journalArticlepeer-review

36 Scopus citations


The proliferation-specific transcription factor complex HiNF-D interacts with sequence specificity in a proximal promoter element of the human H4 histone gene FO108, designated Site II. The occupancy of Site II by HiNF-D has been implicated in proper transcription initiation and as a component of the cell cycle regulation of this gene. In the present study we have investigated the role of the HiNF-D/Site II interaction in controlling the level of H4 histone gene transcription during modifications of normal cellular growth. HiNF-D binding activity is present at high levels in rapidly proliferating cultures of human diploid fibroblasts and is reduced to less than 2% upon the cessation of proliferation induced by serum deprivation of sparsely populated fibroblast cultures. Density-dependent quiescence also abolishes HiNF-D binding activity. Downregulation of transcription from the H4 gene occurs concomitant with the loss of the HiNF-D/Site II interaction, further suggesting a functional relationship between Site II occupancy and the capacity for transcription. Serum stimulation of quiescent preconfluent cells results in an increase in HiNF-D binding activity as the cells are resuming DNA synthesis and H4 histone gene transcription. Density-inhibited quiescent cells respond to serum stimulation with only a minimal increase in the HiNF-D binding activity, 30% of maximal levels. However, H4 histone gene transcription is stimulated to a level equal to that detected in extracts of the sparsely populated serum-stimulated cultures. These results suggest that there is a threshold level of HiNF-D binding activity necessary for the activation of H4 histone gene transcription. Additionally, these findings suggest that there may be a mechanism repressing HiNF-D binding activity in the density-inhibited cultures which is not operative in the sparsely populated, serum-deprived cultures. Density-inhibited cultures may have reached a state analogous to the initial steps of differentiation and have invoked a series of mechanisms to decrease expression of proliferation-specific factors. Serum stimulation is able to overcome the one mechanism downregulating HiNF-D in both sparsely populated and density-inhibited quiescent cultures but is unable to reverse the repression of proliferation-specific factors that occurs in density-inhibited cultures. These results are consistent with the presence of at least two levels of control over the HiNF-D/Site II interaction which are responsive to and reflect the proliferative state of the cell and the extent to which the cell exhibits properties associated with differentiation.

Original languageEnglish (US)
Pages (from-to)2812-2818
Number of pages7
Issue number10
StatePublished - Mar 1 1992

ASJC Scopus subject areas

  • Biochemistry


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