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Cited by 548Genomics and Chromatin DynamicsCancer-related molecular mechanisms researchEstrogen and related hormone effects

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

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Lam, Michael T. Y., Cho, Han, Lesch, Hanna P., Gosselin, David, Heinz, Sven, Tanaka-Oishi, Yumiko, Benner, Christopher, Kaikkonen, Minna U. +8 more·2013·Nature
DOI 10.1038/nature12209PMC PMC3839578
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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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  • The majority of active enhancers are themselves transcribed, producing enhancer RNAs in a bi-directional manner.

    “The majority of active enhancers are themselves transcribed, producing enhancer RNAs (eRNAs) in a bi-directional manner [73–77].”

    From Transcriptional enhancers and their communication with gene promoters (2021) · cites this paper as [75]

    The passage reporting GRO-Seq results (section labeled Abstract; page unavailable) found eRNA initiation at 76% of Rev-Erb binding sites in enhancer-like regions and bidirectional transcription at 56% of those sites. This supports the pattern in the studied macrophage-associated sites, but not the broader claim that a majority of active enhancers generally are transcribed bidirectionally. (LLM, conf=0.86)

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Research works printed but not linked: 27

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Authors
Lam, M. T. Y., Cho, H., Lesch, H. P., Gosselin, D., Heinz, S., Tanaka-Oishi, Y., Benner, C., Kaikkonen, M. U., Kim, A. S., Kosaka, M., Lee, C. Y., Watt, A., Grossman, T. R., Rosenfeld, M. G., Evans, R. M., & Glass, C. K.
Affiliations
  • University of California San Diego (US)
  • Salk Institute for Biological Studies (US)
  • Ionis Pharmaceuticals (United States) (US)
  • Howard Hughes Medical Institute (US)
Corresponding author
Glass, Christopher K.
ORCID
Venue
Nature
Publisher
Springer Science and Business Media LLC
Published
2013-06
Volume
498
Issue
7455
Pages
511-515
ISSN
  • 0028-0836 (ISSN-L)
  • 1476-4687
DOI
10.1038/nature12209
PMC
PMC3839578
OpenAlex
W1985105928
Cited by
548
References
3
Citations by year
2026: 26 · 2025: 26 · 2024: 26 · 2023: 22 · 2022: 29 · 2021: 53 · 2020: 42 · 2019: 41 · 2018: 41 · 2017: 42 · 2016: 47 · 2015: 62 · 2014: 64 · 2013: 27
FWCI
25.11
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Nature (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
Funders
  • Howard Hughes Medical Institute
  • National Heart, Lung, and Blood Institute (HL105278, R01HL105278, HL-088093, P01HL088093)
  • National Cancer Institute (CA014195, R01CA173903, R01CA052599, CA17390, P30CA014195, CA 52599)
  • National Institute of General Medical Sciences (T32GM008666, T32GM007198)
  • National Institute of Diabetes and Digestive and Kidney Diseases (DK063491, R37DK057978, DK057978, DK091183, P01DK074868, U19DK062434, P30DK063491, R01DK018477, R01DK091183)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer-related molecular mechanisms research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
Keywords
bidirectional transcription, NR1D1, macrophages, enhancer function, transcriptional repression, nascent RNA, macrophage lineage, circadian rhythm, inflammation, oestrogen receptor, breast cancer
MeSH terms
Alleles, Animals, Base Sequence, Binding Sites, Enhancer Elements, Genetic, Macrophages, Organ Specificity, Promoter Regions, Genetic, RNA, Messenger, Transcription, Genetic, Down-Regulation, Response Elements, Mice, Gene Knockdown Techniques, Nuclear Receptor Subfamily 1, Group D, Member 1

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