The DOI matches its Crossref record; 38 of the 38 references it cites were found in a registry or an index.
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 (eRNAs) in a bi-directional manner [73–77].”
From Transcriptional enhancers and their communication with gene promoters (2021) · cites this paper as [77]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“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]
Experimental — accuracy not yet measuredIn the citing paper
“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
In the citing paper
“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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Citations
Cites
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High-Resolution Profiling of Histone Methylations in the Human Genome
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“To generate a set of random peaks matching the CBP peaks we did the following for each intragenic peak: (1) calculate the distance d to the TSS of the overlapping gene; (2) select a gene g at random; (3) place the new random region d base pairs downstream of the TSS of gene g; (4) if d is larger than the length of g t…”
InfluentialHistone modifications at human enhancers reflect global cell-type-specific gene expression
Heintzman, N. D., Hon, G. C., Hawkins, R. D., Kheradpour, P., Stark, A., Harp, L. F., Ye, Z., Lee, L. K., Stuart, R. K., Ching, C. W., et al. (2009) · Nature · doi:10.1038/nature07829 · Cited by 2,533
ChIP–seq: advantages and challenges of a maturing technology
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Expression of a β-globin gene is enhanced by remote SV40 DNA sequences
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ChIP-seq accurately predicts tissue-specific activity of enhancers
Visel, A., Blow, M. J., Li, Z., Zhang, T., Akiyama, J. A., Holt, A., Plajzer-Frick, I., Shoukry, M., Wright, C., Chen, F., et al. (2009) · Nature · doi:10.1038/nature07730 · Cited by 1,639
A high-resolution map of active promoters in the human genome
Kim, T. H., Barrera, L. O., Zheng, M., Qu, C., Singer, M. A., Richmond, T., Wu, Y., Green, R. D., & Ren, B. (2005) · Nature · doi:10.1038/nature03877 · Cited by 954
Self-citation
Research works printed but not linked: 3
- Kawashima, T. et al. Synaptic activity-responsive element in the Arc/Arg3.1 promoter essential for synapse-to-nucleus signaling in activated neurons. Proc. Natl Acad. Sci. USA 106, 316–321 (2009) · DOI
- Robertson, A. G. et al. Genome-wide relationship between histone H3 lysine 4 mono- and tri-methylation and transcription factor binding. Genome Res. 18, 1906–1917 (2008) · DOI · Paper page
- Lin, Y. et al. Activity-dependent regulation of inhibitory synapse development by Npas4. Nature 455, 1198–1204 (2008) · DOI · Paper page
Cited by
Sorted by citations
Landscape of transcription in human cells
Djebali, S., Davis, C. A., Merkel, A., Dobin, A., Lassmann, T., Mortazavi, A., Tanzer, A., Lagarde, J., Lin, W., Schlesinger, F., et al. (2012) · Nature · doi:10.1038/nature11233 · Cited by 5,187
Derrien, T., Johnson, R., Bussotti, G., Andrea Tanzer, A., Djebali, S., Tilgner, H., Guernec, G., Martin, D., Merkel, A., Knowles, D. G., et al. (2012) · Genome Research · doi:10.1101/gr.132159.111 · Cited by 5,135
Gene regulation by long non-coding RNAs and its biological functions
Statello, L., Guo, C.-J., Chen, L.-L., & Huarte, M. (2021) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-020-00315-9 · Cited by 4,991
Molecular Mechanisms of Long Noncoding RNAs
Wang, K., & Chang, H. Y. (2011) · Molecular Cell · doi:10.1016/j.molcel.2011.08.018 · Cited by 4,462
Histone H3K27ac separates active from poised enhancers and predicts developmental state
Creyghton, M. P., Cheng, A. W., Welstead, G. G., Kooistra, T., Carey, B. W., Steine, E. J., Hanna, J., Lodato, M. A., Frampton, G. M., Sharp, P. A., et al. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1016071107 · Cited by 4,302
Metadata
- 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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