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Cited by 350Genomics and Chromatin DynamicsChromatin Remodeling and CancerEpigenetics and DNA Methylation

Widespread transcriptional pausing and elongation control at enhancers

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Henriques, Telmo, Scruggs, Benjamin S., Inouye, Michiko O., Muse, Ginger W., Williams, Lucy H., Burkholder, Adam B., Lavender, Christopher A., Fargo, David C. +1 more·2018·Genes & Development
DOI 10.1101/gad.309351.117PMC PMC5828392
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Abstract

Regulation by gene-distal enhancers is critical for cell type-specific and condition-specific patterns of gene expression. Thus, to understand the basis of gene activity in a given cell type or tissue, we must identify the precise locations of enhancers and functionally characterize their behaviors. Here, we demonstrate that transcription is a nearly universal feature of enhancers in Drosophila and mammalian cells and that nascent RNA sequencing strategies are optimal for identification of both enhancers and superenhancers. We dissect the mechanisms governing enhancer transcription and discover remarkable similarities to transcription at protein-coding genes. We show that RNA polymerase II (RNAPII) undergoes regulated pausing and release at enhancers. However, as compared with mRNA genes, RNAPII at enhancers is less stable and more prone to early termination. Furthermore, we found that the level of histone H3 Lys4 (H3K4) methylation at enhancers corresponds to transcriptional activity such that highly active enhancers display H3K4 trimethylation rather than the H3K4 monomethylation considered a hallmark of enhancers. Finally, our work provides insights into the unique characteristics of superenhancers, which stimulate high-level gene expression through rapid pause release; interestingly, this property renders associated genes resistant to the loss of factors that stabilize paused RNAPII.

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  • The correlation between functional activity measured at scale (e.g. via MPRAs) and the annotations typically used to call enhancers is modest at best.

    “Furthermore, to the extent that functional activity has been measured at scale, e.g. via MPRAs, its correlation with the annotations typically used to call enhancers is modest at best106-108.”

    From Towards a comprehensive catalogue of validated and target-linked human enhancers (2020) · cites this paper as [106]

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References 58 · Cited by 350

Research works printed but not linked: 46

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Authors
Henriques, T., Scruggs, B. S., Inouye, M. O., Muse, G. W., Williams, L. H., Burkholder, A. B., Lavender, C. A., Fargo, D. C., & Adelman, K.
Affiliations
National Institutes of Health (US)
Corresponding author
Adelman, Karen
ORCID
Venue
Genes & Development
Publisher
Cold Spring Harbor Laboratory
Published
2018-01-01
Volume
32
Issue
1
Pages
26-41
ISSN
  • 0890-9369 (ISSN-L)
  • 1549-5477
DOI
10.1101/gad.309351.117
PMC
PMC5828392
OpenAlex
W2786204582
Cited by
350
References
58
Citations by year
2026: 21 · 2025: 31 · 2024: 39 · 2023: 41 · 2022: 49 · 2021: 51 · 2020: 44 · 2019: 37 · 2018: 37
Type
posted content
Language
en
Open access
Licence
cc-by-nc
Locations
  • Genes & Development (publishedVersion, cc-by-nc)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • HighWire Press Open Archive (submittedVersion)
Funders
  • National Institutes of Health
  • National Institute of Environmental Health Sciences (Z01297, ES101987)
  • Harvard Medical School
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
Keywords
enhancer transcription, super-enhancers, RNA polymerase II pausing, transcription elongation, H3K4 methylation, H3K4 trimethylation, early termination, nascent RNA sequencing, enhancer identification, Drosophila, mammalian cells, cell type-specific gene expression
MeSH terms
Animals, Chromatin, Chromosomal Proteins, Non-Histone, Drosophila, Enhancer Elements, Genetic, Gene Expression Regulation, Histones, Promoter Regions, Genetic, RNA Polymerase II, Transcription, Genetic, RNA, Untranslated, Transcription Initiation Site, Drosophila Proteins, Transcriptional Elongation Factors, Mice, Embryonic Stem Cells, Transcription Elongation, Genetic

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