Widespread transcription at neuronal activity-regulated enhancers
Open accessAbstract
We used genome-wide sequencing methods to study stimulus-dependent enhancer function in mouse cortical neurons. We identified approximately 12,000 neuronal activity-regulated enhancers that are bound by the general transcriptional co-activator CBP in an activity-dependent manner. A function of CBP at enhancers may be to recruit RNA polymerase II (RNAPII), as we also observed activity-regulated RNAPII binding to thousands of enhancers. Notably, RNAPII at enhancers transcribes bi-directionally a novel class of enhancer RNAs (eRNAs) within enhancer domains defined by the presence of histone H3 monomethylated at lysine 4. The level of eRNA expression at neuronal enhancers positively correlates with the level of messenger RNA synthesis at nearby genes, suggesting that eRNA synthesis occurs specifically at enhancers that are actively engaged in promoting mRNA synthesis. These findings reveal that a widespread mechanism of enhancer activation involves RNAPII binding and eRNA synthesis.
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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 [77]
The Transcription at enhancers section reports that eRNAs are produced bi-directionally at neuronal activity-regulated enhancers. It does not support the claim that a majority of active enhancers are transcribed: the Methods Summary reports detectable eRNAs at 44% of extragenic enhancers, and the findings are limited to neuronal enhancers. Page numbers are not provided in our copy. (LLM, conf=0.89)
Experimental — accuracy not yet measuredEnhancers are sites for the assembly of a complete Pol II preinitiation complex and bidirectional transcription of short-lived enhancer RNA (eRNA).
“Relatively recently, enhancers have been shown to be sites for the assembly of a complete Pol II preinitiation complex and bidirectional transcription of short-lived enhancer RNA (eRNA) [57,58,59].”
From Enhancer Function in the 3D Genome (2023) · cites this paper as [58]
The 'Transcription at enhancers' section (page unavailable) reports RNAPII binding at a subset of neuronal enhancers and short eRNAs synthesized bidirectionally from enhancer centers. It does not establish assembly of a complete Pol II preinitiation complex or show that the eRNAs are short-lived; short transcript length and changing RNA levels do not establish lifetime. (LLM, conf=0.87)
Experimental — accuracy not yet measuredNeuronal depolarization communication proceeds through various signaling cascades and regulates intranuclear events such as enhancer recruitment, transcription factor activation, and alternative pre-mRNA splicing.
“Communication of neuronal depolarization proceeds by a variety of signaling cascades and regulates intranuclear events such as enhancer recruitment (Kim et al., 2010), transcription factor activation (Ebert and Greenberg, 2013) and alternative pre-mRNA splicing (Li et al., 2007).”
From Unifying Views of Autism Spectrum Disorders: A Consideration of Autoregulatory Feedback Loops (2016) · cites this paper as Kim et al., 2010
A recent study identified thousands of neuronal activity-regulated enhancers of transcription that could potentially be sites of human variation leading to ASD.
“Of note, therefore, is a recent study that identified thousands of neuronal activity-regulated enhancers of transcription that could potentially be sites of human variation that lead to ASD36.”
From Activity-dependent neuronal signalling and autism spectrum disorder (2013) · cites this paper as [36]
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- Authors
- Kim, T.-K., Hemberg, M., Gray, J. M., Costa, A. M., Bear, D. M., Wu, J., Harmin, D. A., Laptewicz, M., Barbara-Haley, K., Kuersten, S., Markenscoff-Papadimitriou, E., Kuhl, D., Bito, H., Worley, P. F., Kreiman, G., & Greenberg, M. E.
- Affiliations
- Harvard University (US)
- Boston Children's Hospital (US)
- Johns Hopkins University (US)
- Epicentre (FR)
- Universität Hamburg (DE)
- The University of Tokyo (JP)
- Corresponding author
- Greenberg, Michael E.
- ORCID
- Venue
- Nature
- Published
- 2010-04-14
- Volume
- 465
- Issue
- 7295
- Pages
- 182-187
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC3020079
- OpenAlex
- W2014787267
- Cited by
- 2,450
- References
- 38
- Citations by year
- 2026: 70 · 2025: 126 · 2024: 138 · 2023: 121 · 2022: 152 · 2021: 180 · 2020: 169 · 2019: 151 · 2018: 158 · 2017: 167 · 2016: 155 · 2015: 204 · 2014: 175 · 2013: 187 · 2012: 140
- FWCI
- 62.71
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- RePEc: Research Papers in Economics (submittedVersion)
- Open Access System for Information Sharing (Pohang University of Science and Technology) (submittedVersion)
- Funders
- National Institutes of Health (1dp2od006461-01)
- National Institute of Mental Health (R01MH053608, MH-053608)
- National Eye Institute (R21EY019710)
- National Institute of Neurological Disorders and Stroke (NS028829, R01NS028829, R37NS028829)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (P30HD018655)
- 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 › Molecular Biology › RNA Research and Splicing
- Keywords
- enhancer RNA, CBP, RNA polymerase II, enhancer activation, H3K4 monomethylation, cortical neurons, electrical activity, gene expression regulation, mouse brain
- MeSH terms
- Animals, Cytoskeletal Proteins, Enhancer Elements, Genetic, Gene Expression Regulation, Histones, Methylation, Mice, Inbred C57BL, Nerve Tissue Proteins, Neurons, RNA Polymerase II, Transcription, Genetic, Consensus Sequence, Genes, fos, Genes, Reporter, RNA, Untranslated, CREB-Binding Protein, Mice, Basic Helix-Loop-Helix Proteins, Basic Helix-Loop-Helix Transcription Factors
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