Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 112, Issue 3, Pages E297-E302Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1424028112
Keywords
super enhancers; enhancer RNAs; transcription factors; GRO-Seq; macrophage
Categories
Funding
- Pioneer Postdoctoral Endowment Fellowship
- National Institutes of Health [DK057978, DK090962, HL088093, HL105278, ES010337]
- Stand Up to Cancer Dream Team Translational Cancer Research Grant
- Program of the Entertainment Industry Foundation [SU2C-AACR-DT0509]
- Glenn Foundation for Medical Research
- Leona M. and Harry B. Helmsley Charitable Trust
- Ipsen/Biomeasure
- California Institute for Regenerative Medicine
- Ellison Medical Foundation
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Enhancers are critical genomic elements that define cellular and functional identity through the spatial and temporal regulation of gene expression. Recent studies suggest that key genes regulating cell type-specific functions reside in enhancer-dense genomic regions (i.e., super enhancers, stretch enhancers). Here we report that enhancer RNAs (eRNAs) identified by global nuclear run-on sequencing are extensively transcribed within super enhancers and are dynamically regulated in response to cellular signaling. Using Toll-like receptor 4 (TLR4) signaling in macrophages as a model system, we find that transcription of super enhancer-associated eRNAs is dynamically induced at most of the key genes driving innate immunity and inflammation. Unexpectedly, genes repressed by TLR4 signaling are also associated with super enhancer domains and accompanied by massive repression of eRNA transcription. Furthermore, we find each super enhancer acts as a single regulatory unit within which eRNA and genic transcripts are coordinately regulated. The key regulatory activity of these domains is further supported by the finding that super enhancer-associated transcription factor binding is twice as likely to be conserved between human and mouse than typical enhancer sites. Our study suggests that transcriptional activities at super enhancers are critical components to understand the dynamic gene regulatory network.
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