Master Transcription Factors and Mediator Establish Super-Enhancers at Key Cell Identity Genes

By Warren A. Whyte, David A. Orlando, Denes Hnisz, B. Abraham, Charles Y. Lin, M. Kagey, P. Rahl, Tong Ihn Lee, Richard A. Young. Cell, 2013

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Summary 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). We report here that the ESC master transcription factors form unusual enhancer domains at most genes that control the pluripotent state. These domains, which we call super-enhancers, consist of clusters of enhancers that are densely occupied by the master regulators and Mediator. Super-enhancers differ from typical enhancers in size, transcription factor density and content, ability to activate transcription, and sensitivity to perturbation. 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. In other more differentiated cells, super-enhancers containing cell type-specific master transcription factors are also found at genes that define cell identity. Super-enhancers thus play key roles in the control of mammalian cell identity.

Subfields: Molecular Biology

View Paper: https://www.semanticscholar.org/paper/8a903ba823bd4f26190bbf17ae9645837dcb2c74

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Citations in the corpus

Transcriptional Addiction in Cancer (2017, neutral): “Bound by master TFs, clusters of enhancers known as super-enhancers (SEs) regulate genes that play prominent roles in cell identity or specialized cellular function (Chapuy et al., 2013; Hnisz et al., 2013; Hnisz et al., 2015; Whyte et al., 2013).”
Chromatin stretch enhancer states drive cell-specific gene regulation and harbor human disease risk variants (2013, background): “While this manuscript was in preparation, two reports (30, 31) described the presence of large enhancers in mouse cells and human cancer cell lines associated with highly expressed cell identity genes and densely occupied by the Mediator coactivator complex.”
Control of cell identity genes occurs in insulated neighborhoods in mammalian chromosomes (2014, positive): “The master transcription factors (TFs) OCT4, SOX2 and NANOG (OSN) form super-enhancers at most cell identity genes, including those encoding the master TFs themselves; these super-enhancers contain exceptional levels of transcription apparatus and drive high-level expression of associated genes (Hni”
Mediator and RNA polymerase II clusters associate in transcription-dependent condensates (2018, background): “S15) to investigate whether active transcription could be observed at Esrrb, one of the top SE-controlled genes in mESCs (29) (Fig.”
Coactivator condensation at super-enhancers links phase separation and gene control (2018, methodology): “SEs are established by the binding of master TFs to enhancer clusters (14, 15).”
Chromatin Potential Identified by Shared Single-Cell Profiling of RNA and Chromatin (2020, background): “…high density of peak-gene associations significantly overlapped known super-enhancers (Adam et al., 2015; Figure 3C; Table S5; 2.1-fold enrichment, p = 10 −238 , hypergeometric test)—enhancer regions that are cell-type-specific and highly enriched in histone H3K27 acetylation (Whyte et al., 2013).”