C/EBPβ Activates E2F-regulated Genes in Vivo via Recruitment of the Coactivator CREB-binding Protein/P300

Abstract

The E2F transcription factors play an essential role in regulating the G(1)- to S-phase transition of the cell cycle. Previous studies have identified the importance of interactions between E2Fs and other transcription factors as a mechanism for transcriptional control of a subset of E2F regulated target genes. However, the mechanisms responsible for E2F target gene specificity remain incompletely understood. Here we report that in a mammalian in vivo model of synchronized proliferation, C/EBPbeta occupancy on the promoters of E2F-regulated growth-related genes increases as a function of cell cycle progression. C/EPBbeta binding to these promoters is associated with recruitment of the coactivator CBP/p300, histone H4 acetylation, and maximal activation of E2F target genes. Moreover, binding of CBP/p300 to E2F targets is markedly reduced in C/EBPbeta null mice, resulting in reduced expression of E2F regulated genes. These findings identify C/EBPbeta as a direct activator of E2F target genes in mammalian cell cycle progression through a mechanism that involves recruitment of CBP/p300. The demonstration of a functional link between C/EBPbeta and CBP/p300 for E2F target gene activation provides a potential mechanism for how coactivators such as CBP/p300 can be selectively recruited to E2F target genes in response to tissue-specific growth stimuli.