H) Box plots of Oct4, Sox2, Nanog, Klf4 and Esrrb ChIP-Seq density at constituent enhancers within the 8,563 typical enhancers and the 231 super-enhancers. Each metagene is centered on a constituent enhancer with 2kb surrounding the constituent enhancer region. G) Metagenes of Oct4, Sox2, Nanog, Klf4 and Esrrb ChIP-Seq density across the constituent enhancers within the 8,563 typical enhancers and the 231 super-enhancer regions. F) ChIP-Seq binding profiles for Oct4, Sox2, Nanog, Klf4, and Esrrb at the Gck and miR-290-295 loci in ESCs. The x- and y-axes are adjusted so that the differences in the distribution of each of the enhancer features can be visualized. The enhancers on the X-axis are ranked for each enhancer feature independently (i.e., the exact enhancer at position 8000 is different for each enhancer feature).
For each enhancer feature, the plot was normalized by dividing the ChIP-Seq signal at each ESC enhancer by the maximum ChIP-Seq signal. E) Distribution of Mediator, H3K27ac, H3K4me1, DNaseI hypersensitivity, and OSN normalized ChIP-Seq signal across a subset of the 8,794 ESC enhancers. Fold difference at enhancer constituents refers to the mean ChIP-Seq density (reads per million per base pair) at super-enhancer constituents divided by the mean ChIP-Seq density at typical enhancer constituents. Fold difference at enhancers refers to the mean ChIP-Seq signal (total reads) at super-enhancers divided by the mean ChIP-Seq signal at typical enhancers. ChIP-Seq fold difference for enhancer features Mediator, H3K27ac, H3K4me1, and DNaseI hypersensitivity at super-enhancers versus typical enhancers are displayed below the metagenes. Metagenes are centered on the enhancer region (703 base pairs for typical enhancers and 8.7kb for super-enhancers), with 3kb surrounding each enhancer region. D) Metagenes of Mediator ChIP-Seq density (reads per million per base pair) across the 8,563 typical enhancers and the 231 super-enhancers. Mediator occupancy is not evenly distributed across the enhancer regions, with a subset of enhancers (the 231 super-enhancers) containing exceptionally high amounts of Mediator. C) Distribution of Mediator ChIP-Seq signal (total reads) across the 8,794 ESC enhancers. Enhancer bars and scale bars are depicted above the binding profiles. Gene models are depicted below the binding profiles. All rights reserved.Ī,B) ChIP-Seq binding profiles (reads per million per base pair) for ESC transcription factors Oct4, Sox2, and Nanog (OSN), and the Mediator coactivator (Med1) at the Gck and miR-290-295 loci in ESCs. Super-enhancers thus play key roles in the control of mammalian cell identity.Ĭopyright © 2013 Elsevier Inc. In other more differentiated cells, super-enhancers containing cell-type-specific master transcription factors are also found at genes that define cell identity. Reduced levels of Oct4 or Mediator cause preferential loss of expression of super-enhancer-associated genes relative to other genes, suggesting how changes in gene expression programs might be accomplished during development.
Super-enhancers differ from typical enhancers in size, transcription factor density and content, ability to activate transcription, and sensitivity to perturbation. These domains, which we call super-enhancers, consist of clusters of enhancers that are densely occupied by the master regulators and Mediator. We report here that the ESC master transcription factors form unusual enhancer domains at most genes that control the pluripotent state. Master transcription factors Oct4, Sox2, and Nanog bind enhancer elements and recruit Mediator to activate much of the gene expression program of pluripotent embryonic stem cells (ESCs).
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