Transcriptional activation of the histone nuclear factor P (HiNF-P) gene by HiNF-P and its cyclin E/CDK2 responsive co-factor p220^NPAT defines a novel autoregulatory loop at the G1/S phase transition

Histone nuclear factor P (HiNF-P) activates histone H4 gene transcription at the G1/S phase transition upon association with its cyclin E/CDK2 responsive co-factor p220^NPAT. Here we characterize the gene regulatory pathways that control the proliferation-related expression of HiNF-P. The HiNF-P locus contains a single TATA-less 0.6 kbp promoter with multiple phylogenetically conserved transcription factor recognition motifs. Transient reporter gene assays with HiNF-P promoter deletions show that there are at least three distinct activating regions (- 387/- 201, - 201/- 100 and - 100/- 1) that support maximal transcription. HiNF-P gene transcription is activated by SP1 through the - 100/- 1 domain and repressed by E2F1 through the - 201/- 100 domain. The multifunctional co-regulators CBP and p300 also stimulate HiNF-P gene transcription through the - 201/- 1 core promoter. Importantly, the HiNF-P promoter is activated by both HiNF-P and p220^NPAT. This autoregulatory activation is further enhanced by cyclin E and CDK2, while blocked by CDK inhibition (i.e., p57^KIP2 p27^KIP1, p21^CIP). Thus, the HiNF-P gene is a key non-histone target of p220^NPAT and HiNF-P. The dependence of HiNF-P gene transcription on cyclin E/CDK2/p220^NPAT signaling defines a novel feed-forward loop that may sustain HiNF-P expression in proliferating cells to support the cell cycle regulated synthesis of histone H4 proteins.