Host cell factor-1(HCF-1) was first discovered as a cellular cofactor in the VP16-induced complex, a multi-protein DNA complex that forms on immediate early gene promoters of herpes simplex virus (HSV) to activate viral gene transcription. Subsequent research has revealed HCF-1 to be an abundant chromatin-associated protein that regulates various stages of the cell cycle. Recent reports show that HCF-1 interacts with diverse E2F proteins to induce cell-cycle-specific transcription. HCF-1 can act as a scaffold to a variety of histone-modifying proteins and these HCF-1-E2F-containing multi-protein complexes can bring about context-dependent activation or repression of transcription. In this review we examine the diversity of HCF-E2F interactions and the variety of multi-protein complexes it occurs in, to influence the local chromatin landscape at the E2F-promoters.
The Histone 3 lysine 4 methylation (H3K4me3) mark closely correlates with active transcription. E2F-responsive promoters display dynamic changes in H3K4 methylation during the course of cell cycle progression. However, how and when these marks are reset, is not known. Here we show that the retinoblastoma binding protein RBP2/KDM5A, capable of removing tri-methylation marks on H3K4, associates with the E2F4 transcription factor via the pocket protein—p130—in a cell-cycle-stage specific manner. The association of RBP2 with p130 is LxCxE motif dependent. RNAi experiments reveal that p130 recruits RBP2 to E2F-responsive promoters in early G1 phase to bring about H3K4 demethylation and gene repression. A point mutation in LxCxE motif of RBP2 renders it incapable of p130-interaction and hence, repression of E2F-regulated gene promoters. We also examine how RBP2 may be recruited to non-E2F responsive promoters. Our studies provide insight into how the chromatin landscape needs to be adjusted rapidly and periodically during cell-cycle progression, concomitantly with temporal transcription, to bring about expression/repression of specific gene sets.
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