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.