title: Inflammation-sensitive super enhancers form domains of coordinately regulated enhancer RNAs.
abstract: 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.
authors.affiliation: Gene Expression Laboratory.
authors.forename: Nasun
authors.initials: N
authors.lastname: Hah
authors.affiliation: Razzavi Newman Integrated Genomics and Bioinformatics Core, and.
authors.forename: Chris
authors.initials: C
authors.lastname: Benner
authors.affiliation: Gene Expression Laboratory.
authors.forename: Ling-Wa
authors.initials: LW
authors.lastname: Chong
authors.affiliation: Gene Expression Laboratory.
authors.forename: Ruth T
authors.initials: RT
authors.lastname: Yu
authors.affiliation: Gene Expression Laboratory.
authors.forename: Michael
authors.initials: M
authors.lastname: Downes
authors.affiliation: Gene Expression Laboratory, Howard Hughes Medical Institute, The Salk Institute for Biological Studies, La Jolla, CA 92037 evans@salk.edu.
authors.forename: Ronald M
authors.initials: RM
authors.lastname: Evans
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004742:Enhancer Elements, Genetic; D006801:Humans; D007249:Inflammation / Q000378:metabolism*; D051379:Mice; D012313:RNA / Q000235:genetics*; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: D051197:Toll-Like Receptor 4; D012313:RNA
keywords: GRO-Seq; enhancer RNAs; macrophage; super enhancers; transcription factors