title: Rev-Erbs repress macrophage gene expression by inhibiting enhancer-directed transcription.
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.
authors.affiliation: Department of Cellular and Molecular Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093, USA.
authors.forename: Michael T Y
authors.initials: MT
authors.lastname: Lam
authors.forename: Han
authors.initials: H
authors.lastname: Cho
authors.forename: Hanna P
authors.initials: HP
authors.lastname: Lesch
authors.forename: David
authors.initials: D
authors.lastname: Gosselin
authors.forename: Sven
authors.initials: S
authors.lastname: Heinz
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Tanaka-Oishi
authors.forename: Christopher
authors.initials: C
authors.lastname: Benner
authors.forename: Minna U
authors.initials: MU
authors.lastname: Kaikkonen
authors.forename: Aneeza S
authors.initials: AS
authors.lastname: Kim
authors.forename: Mika
authors.initials: M
authors.lastname: Kosaka
authors.forename: Cindy Y
authors.initials: CY
authors.lastname: Lee
authors.forename: Andy
authors.initials: A
authors.lastname: Watt
authors.forename: Tamar R
authors.initials: TR
authors.lastname: Grossman
authors.forename: Michael G
authors.initials: MG
authors.lastname: Rosenfeld
authors.forename: Ronald M
authors.initials: RM
authors.lastname: Evans
authors.forename: Christopher K
authors.initials: CK
authors.lastname: Glass
mesh_terms: D000483:Alleles; D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D015536:Down-Regulation / Q000235:genetics*; D004742:Enhancer Elements, Genetic / Q000235:genetics*; D055785:Gene Knockdown Techniques; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D056953:Nuclear Receptor Subfamily 1, Group D, Member 1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D009928:Organ Specificity; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020218:Response Elements / Q000235:genetics; D014158:Transcription, Genetic / Q000235:genetics*
chemical_list: C498262:Nr1d1 protein, mouse; D056953:Nuclear Receptor Subfamily 1, Group D, Member 1; D012333:RNA, Messenger