Human H4 histone gene transcription requires the proliferation-specific nuclear factor HiNF-D. Auxiliary roles for HiNF-C (Sp1-like) and HiNF-A (high mobility group-like).

The proximal promoter of the human H4 histone gene F0108 contains two in vivo protein binding domains, sites I and II. In this report we show that these sequences interact with three nuclear factors: HiNF-D, HiNF-C, and HiNF-A. HiNF-C is a metal ion-requiring protein that binds to an Sp1 consensus binding site. HiNF-C and HiNF-A bind independently to the distally located site I, possibly in conjunction with other proteins, and deletion of site I reduces transcription rates 4- to 6-fold in vitro. Factor HiNF-D binds to an H4 histone-specific element (5'-dGGTPyPyTCAATCNG-GTCCG, where Py indicates pyrimidine) present in site II that has previously been shown to be essential for in vivo expression of this H4 histone gene. All three binding activities are present in human HeLa S3 cells throughout the cell cycle and in exponentially growing mouse C127 and human HL60 cells. This result is consistent with the transcription of H4 histone genes throughout the cell cycle. However, unlike HiNF-A and HiNF-C, HiNF-D is not present in terminally differentiated HL60 cells, in which histone gene transcription is down-regulated. These findings suggest a crucial role for HiNF-D, with an auxiliary role for HiNF-C and possibly HiNF-A, in the regulation of H4 histone gene transcription. Furthermore, the conservation of potential HiNF-D binding sites in mammalian H4 histone gene promoters suggests that HiNF-D has an essential role in the coordinate transcriptional down-regulation of the H4 histone multigene subfamily during the shutdown of proliferation.