Rev-Erb-α and Rev-Erb-β are nuclear receptors that regulate the expression of genes involved in the control of circadian rhythm1,2, metabolism3,4 and inflammatory responses5. Rev-Erbs function as transcriptional repressors by recruiting nuclear receptor co-repressor (NCoR)–HDAC3 complexes to Rev-Erb response elements in enhancers and promoters of target genes6,7,8, but the molecular basis for cell-specific programs of repression is not known. Here we present evidence that in mouse macrophages Rev-Erbs regulate target gene expression by inhibiting the functions of distal enhancers that are selected by macrophage-lineage-determining factors, thereby establishing a macrophage-specific program of repression. Remarkably, the repressive functions of Rev-Erbs are associated with their ability to inhibit the transcription of enhancer-derived RNAs (eRNAs). Furthermore, targeted degradation of eRNAs at two enhancers subject to negative regulation by Rev-Erbs resulted in reduced expression of nearby messenger RNAs, suggesting a direct role of these eRNAs in enhancer function. By precisely defining eRNA start sites using a modified form of global run-on sequencing that quantifies nascent 5′ ends, we show that transfer of full enhancer activity to a target promoter requires both the sequences mediating transcription-factor binding and the specific sequences encoding the eRNA transcript. These studies provide evidence for a direct role of eRNAs in contributing to enhancer functions and suggest that Rev-Erbs act to suppress gene expression at a distance by repressing eRNA transcription.
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Gene Expression Omnibus
Sequencing data have been deposited in the Gene Expression Omnibus under accession GSE45914.
We thank L. Bautista for assistance with figure preparation. These studies were supported by National Institutes of Health grants CA17390, U19DK62434, DK091183, DK063491, CA014195, DK057978, HL088093, HL105278 and CA52599. M.G.R. and R.M.E. are Investigators of the Howard Hughes Medical Institute. M.T.Y.L. is supported by the University of California, San Diego Medical Scientist Training Program T32 GM007198-37, and Genetics Training Program T32 GM008666, National Institute of General Medical Sciences. M.U.K. was supported by a LeDucq Foundation Fellowship. H.P.L. was supported by the Finnish Cultural Foundation, Instumentarium Foundation, The Paulo Foundation, Paavo Nurmi Foundation, Finnish Foundation for Cardiovascular Research, The Maud Kuistila Memorial Foundation and The Fulbright Center. These studies were also supported by grants from the Leona M. and Harry B. Helmsley Charitable Trust, Samuel Waxman Cancer Research Foundation, the Glenn Foundation for Medical Research, the Ellison Medical Foundation and Ipsen/Biomeasure.
This file contains Supplementary Figures 1-16 and additional references.
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Activation of Rev-erbα attenuates lipopolysaccharide-induced inflammatory reactions in human endometrial stroma cells via suppressing TLR4-regulated NF-κB activation
Acta Biochimica et Biophysica Sinica (2019)