Super-Enhancers Facilitate Gene Regulation by Signaling Pathways

Clusters of enhancers known as super-enhancers have been shown to regulate the transcription of genes implicated in cell identity and are frequently acquired by cancer cells at oncogenes. However, the reasons why super-enhancers have evolved and the relative contributions of their individual constituent enhancers in regulating the expression of associated genes remain incompletely understood. Hnisz, Schuijers, and colleagues found that super-enhancers in murine embryonic stem cells (ESC) were composed of clusters of functional enhancers with ESC-specific activity that was dependent on expression of the pluripotency transcription factor OCT4 (also known as POU5F1). Constituent enhancers within super-enhancers exhibited physical and functional interactions, and deletion of individual constituent enhancers impaired expression of associated genes, indicative of a nonredundant contribution of each enhancer to transcription. Furthermore, in contrast to typical enhancers, super-enhancers in both murine and human ESCs were more frequently bound by terminal transcription factors of signaling pathways that transcriptionally regulate stem-cell identity, including the WNT, TGFβ, and leukemia inhibitory factor pathways, suggesting that the clustered structure of super-enhancers may facilitate response to developmental signaling. Consistent with this idea, perturbation of these pathways resulted in significant changes in the expression of super-enhancer–associated genes that regulate ESC self-renewal and differentiation. In addition, acquired super-enhancers in WNT-dependent colorectal cancer cells, including an oncogene-associated super-enhancer at the MYC locus, were enriched for binding of the terminal WNT transcription factor transcription factor 7-like 2 (also known as TCF4), and genes associated with these super-enhancers were particularly responsive to stimulation or inhibition of oncogenic WNT signaling. Similarly, acquired super-enhancers in estrogen receptor (ER)–positive breast cancer cells were occupied by ERα. These findings support the idea that super-enhancers evolved as a means to enable regulation of pluripotency gene expression by signaling pathways during development and to enhance the expression of tumor-promoting genes in response to oncogenic signaling.

Hnisz D, Schuijers J, Lin CY, Weintraub AS, Abraham BJ, Lee TI, et al. Convergence of developmental and oncogenic signaling pathways at transcriptional super-enhancers. Mol Cell 2015 Mar 19 [Epub ahead of print].