Chromatin-bound RB targets promoters, enhancers, and CTCF-bound loci and is redistributed by cell-cycle progression.

The interaction of RB with chromatin is key to understanding its molecular functions. Here, for first time, we identify the full spectrum of chromatin-bound RB. Rather than exclusively binding promoters, as is often described, RB targets three fundamentally different types of loci (promoters, enhancers, and insulators), which are largely distinguishable by the mutually exclusive presence of E2F1, c-Jun, and CTCF. While E2F/DP facilitates RB association with promoters, AP-1 recruits RB to enhancers. Although phosphorylation in CDK sites is often portrayed as releasing RB from chromatin, we show that the cell cycle redistributes RB so that it enriches at promoters in G1 and at non-promoter sites in cycling cells. RB-bound promoters include the classic E2F-targets and are similar between lineages, but RB-bound enhancers associate with different categories of genes and vary between cell types. Thus, RB has a well-preserved role controlling E2F in G1, and it targets cell-type-specific enhancers and CTCF sites when cells enter S-phase. [Display omitted] • RB associates with E2F-promoters, AP-1 enhancers, and CTCF-insulators • RB-bound promoters and enhancers target different sets of genes • Cell-cycle progression redistributes chromatin-bound RB toward enhancers • RB-bound promoters are conserved while enhancers are cell-type specific Sanidas et al. show that, rather than exclusively targeting E2F-promoters, RB associates with specific groups of promoters, enhancers, and insulators to target different sets of genes. Cell-cycle progression redistributes RB toward cell-type-specific enhancers. PanChIP software confirms that RB associates with distinct transcription factors at different types of loci. [ABSTRACT FROM AUTHOR]