Rev-Erbs repress macrophage gene expression by inhibiting enhancer-directed transcription

MTY Lam, H Cho, HP Lesch, D Gosselin, S Heinz… - Nature, 2013 - nature.com
Nature, 2013nature.com
Abstract Rev-Erb-α and Rev-Erb-β are nuclear receptors that regulate the expression of
genes involved in the control of circadian rhythm,, metabolism, and inflammatory responses.
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 genes,,, 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 …
Abstract
Rev-Erb-α and Rev-Erb-β are nuclear receptors that regulate the expression of genes involved in the control of circadian rhythm,, metabolism, and inflammatory responses. 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 genes,,, 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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