E2F-associated chromatin modifiers and cell cycle control

Abstract

The E2F family of proteins was identified on the basis of its role in promoting the G0 to S phase transition. Research over the past several years has unveiled considerable complexity within the family, with numerous studies pointing to delegation of function for distinct family members. More recent studies highlighted in this review have expanded this picture, suggesting ways in which E2F target gene expression is refined during cell cycle progression by facilitating the acquisition of promoter-specific histone modifications. E2F associated co-activators promote activating histone marks while recruitment of co-repressors associated with E2Fs and the pRB family leads to accretion of inhibitory histone modifications that provoke chromatin compaction.

Figure 1. Speculative model describing co-factors that regulate E2F target genes during the cell cycle

Major complexes discussed in this review are shown, but others may also exist. Interactions between distinct complexes are possible but not yet demonstrated. During cell cycle arrest, the DREAM complex associates with E2F4-p130 and E2F target promoters, whereas it associates with B-MYB in S phase. It remains to be determined if B-MYB-associated DREAM core-complex binds to B-MYB target promoters at this stage of the cycle. The HCF-1 complex promotes gene activation by binding activator E2Fs in S phase, recruiting the HMTase MLL/Set1 to E2F targets. The SWI/SNF complex also changes composition by incorporating ARID1A during quiescence but ARID1B in S phase, when E2F target genes are expressed. In the G0 phase, when cell cycle genes are not expressed, they may acquire a more compact state through the action of L(3)MBTL1. During senescence and terminal differentiation, characterized by an irreversible cell cycle arrest, specific histone marks may be involved, such as tri-methyl H3K27, which is deposited by the Polycomb Repressor Complex 2.