HiNF-P directly links the cyclin E/CDK2/p220^NPAT pathway to histone H4 gene regulation at the G₁/S phase cell cycle transition

Genome replication in eukaryotic cells necessitates the stringent coupling of histone biosynthesis with the onset of DNA replication at the G₁/S phase transition. A fundamental question is the mechanism that links the restriction (R) point late in G₁ with histone gene expression at the onset of S phase. Here we demonstrate that HiNF-P, a transcriptional regulator of replication-dependent histone H4 genes, interacts directly with p220 ^NPAT, a substrate of cyclin E/CDK2, to coactivate histone genes during S phase. HiNF-P and p220 are targeted to, and colocalize at, subnuclear foci (Cajal bodies) in a cell cycle-dependent manner. Genetic or biochemical disruption of the HiNF-P/p220 interaction compromises histone H4 gene activation at the G₁/S phase transition and impedes cell cycle progression. Our results show that HiNF-P and p220 form a critical regulatory module that directly links histone H4 gene expression at the G₁/S phase transition to the cyclin E/CDK2 signaling pathway at the R point.