Stimulus-specific combinatorial functionality of neuronal c-fos enhancers
Open accessAbstract
The c-fos gene (also known as Fos) is induced by a broad range of stimuli and is a reliable marker for neural activity. Its induction mechanism and available reporter mouse lines are based exclusively on c-fos promoter activity. Here we demonstrate that multiple enhancers surrounding the c-fos gene are crucial for ensuring robust c-fos response to various stimuli. Membrane depolarization, brain-derived neurotrophic factor (BDNF) and forskolin activate distinct subsets of the enhancers to induce c-fos transcription in neurons, suggesting that stimulus-specific combinatorial activation of multiple enhancers underlies the broad inducibility of the c-fos gene. Accordingly, the functional requirement of key transcription factors varies depending on the type of stimulation. Combinatorial enhancer activation also occurs in the brain. Providing a comprehensive picture of the c-fos induction mechanism beyond the minimal promoter, our study should help in understanding the physiological nature of c-fos induction in relation to neural activity and plasticity.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
A previously reported activity-dependent enhancer-promoter loop at Fos via 3C-PCR was classified as an activity-induced loop.
“We confirmed that an enhancer–promoter loop that has been reported previously as activity-dependent at Fos via 3C-PCR (ref. 36) was classified here as an activity-induced loop”
From Three-dimensional genome restructuring across timescales of activity-induced neuronal gene expression (2020) · cites this paper as [36]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Topological domains in mammalian genomes identified by analysis of chromatin interactions
Dixon, J. R., Selvaraj, S., Yue, F., Kim, A., Li, Y., Shen, Y., Hu, M., Liu, J. S., & Ren, B. (2012) · Nature · doi:10.1038/nature11082 · Cited by 6,829 · see citing works
Improved vectors and genome-wide libraries for CRISPR screening
Sanjana, N. E., Shalem, O., & Zhang, F. (2014) · Nature Methods · doi:10.1038/nmeth.3047 · Cited by 5,239 · see citing works
Master Transcription Factors and Mediator Establish Super-Enhancers at Key Cell Identity Genes
Whyte, W. A., Orlando, D. A., Hnisz, D., Abraham, B. J., Lin, C. Y., Kagey, M. H., Rahl, P. B., Lee, T. I., & Young, R. A. (2013) · Cell · doi:10.1016/j.cell.2013.03.035 · Cited by 4,143 · see citing works
CRISPR-Mediated Modular RNA-Guided Regulation of Transcription in Eukaryotes
Gilbert, L. A., Larson, M. H., Morsut, L., Liu, Z., Brar, G. A., Torres, S. E., Stern-Ginossar, N., Brandman, O., Whitehead, E. H., Doudna, J. A., et al. (2013) · Cell · doi:10.1016/j.cell.2013.06.044 · Cited by 3,696 · see citing works
Genome-Scale CRISPR-Mediated Control of Gene Repression and Activation
Gilbert, L. A., Horlbeck, M. A., Adamson, B., Villalta, J. E., Chen, Y., Whitehead, E. H., Guimaraes, C., Panning, B., Ploegh, H. L., Bassik, M. C., et al. (2014) · Cell · doi:10.1016/j.cell.2014.09.029 · Cited by 2,728 · see citing works
Stimulation of 3T3 cells induces transcription of the c-fos proto-oncogene
Greenberg, M., & Ziff, E. (1984) · Nature · doi:10.1038/311433a0 · Cited by 2,650 · see citing works
An atlas of active enhancers across human cell types and tissues
The FANTOM Consortium, Andersson, R., Gebhard, C., Miguel-Escalada, I., Hoof, I., Bornholdt, J., Boyd, M., Chen, Y., Zhao, X., Schmidl, C., et al. (2014) · Nature · doi:10.1038/nature12787 · Cited by 2,550 · see citing works
Histone 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 · see citing works
Widespread transcription at neuronal activity-regulated enhancers
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., et al. (2010) · Nature · doi:10.1038/nature09033 · Cited by 2,450 · see citing works
Self-citationThe regulation and function of c-fos and other immediate early genes in the nervous system
Sheng, M., & Greenberg, M. E. (1990) · Neuron · doi:10.1016/0896-6273(90)90106-p · Cited by 2,432 · see citing works
Three-dimensional folding and functional organization principles of the Drosophila genome
Sexton, T., Yaffe, E., Kenigsberg, E., Bantignies, F., Leblanc, B., Hoichman, M., Parrinello, H., Tanay, A., & Cavalli, G. (2012) · Cell · doi:10.1016/j.cell.2012.01.010 · Cited by 1,983 · see citing works
Mapping Patterns of c- fos Expression in the Central Nervous System After Seizure
Morgan, J. I., Cohén, D., Hempstead, J. L., & Curran, T. (1987) · Science · doi:10.1126/science.3037702 · Cited by 1,778 · see citing works
The long-range interaction landscape of gene promoters
Sanyal, A., Lajoie, B. R., Jain, G., & Dekker, J. (2012) · Nature · doi:10.1038/nature11279 · Cited by 1,489 · see citing works
A high-resolution map of the three-dimensional chromatin interactome in human cells
Jin, F., Li, Y., Dixon, J. R., Selvaraj, S., Ye, Z., Lee, A. Y., Yen, C.-A., Schmitt, A. D., Espinoza, C. A., & Ren, B. (2013) · Nature · doi:10.1038/nature12644 · Cited by 1,208 · see citing works
The selection and function of cell type-specific enhancers
Heinz, S., Romanoski, C. E., Benner, C., & Glass, C. K. (2015) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3949 · Cited by 1,010 · see citing works
E-CRISP: fast CRISPR target site identification
Heigwer, F., Kerr, G., & Boutros, M. (2014) · Nature Methods · doi:10.1038/nmeth.2812 · Cited by 866 · see citing works
Flavell, S. W., & Greenberg, M. E. (2008) · Annual Review of Neuroscience · doi:10.1146/annurev.neuro.31.060407.125631 · Cited by 832 · see citing works
Guenthner, C. J., Miyamichi, K., Yang, H. H., Heller, H. C., & Luo, L. (2013) · Neuron · doi:10.1016/j.neuron.2013.03.025 · Cited by 705 · see citing works
Core, L. J., Martins, A. L., Danko, C. G., Waters, C. T., Siepel, A., & Lis, J. T. (2014) · Nature Genetics · doi:10.1038/ng.3142 · Cited by 693 · see citing works
Essential role of brain-derived neurotrophic factor in adult hippocampal function
Monteggia, L. M., Barrot, M., Powell, C. M., Berton, O., Galanis, V., Gemelli, T., Meuth, S., Nagy, A., Greene, R. W., & Nestler, E. J. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0402141101 · Cited by 685 · see citing works
Kaikkonen, M. U., Spann, N. J., Heinz, S., Romanoski, C. E., Allison, K. A., Stender, J. D., Chun, H. B., Tough, D. F., Prinjha, R. K., Benner, C., et al. (2013) · Molecular Cell · doi:10.1016/j.molcel.2013.07.010 · Cited by 672 · see citing works
Activity-dependent regulation of inhibitory synapse development by Npas4
Lin, Y., Bloodgood, B. L., Hauser, J. L., Lapan, A. D., Koon, A. C., Kim, T.-K., Hu, L. S., Malik, A. N., & Greenberg, M. E. (2008) · Nature · doi:10.1038/nature07319 · Cited by 639 · see citing works
Self-citationCDK7 Inhibition Suppresses Super-Enhancer-Linked Oncogenic Transcription in MYCN-Driven Cancer
Chipumuro, E., Marco, E., Christensen, C. L., Kwiatkowski, N. P., Zhang, T., Hatheway, C. M., Abraham, B. J., Sharma, B., Yeung, C. M., Altabef, A. B., et al. (2014) · Cell · doi:10.1016/j.cell.2014.10.024 · Cited by 631 · see citing works
Activity-Dependent Regulation of MEF2 Transcription Factors Suppresses Excitatory Synapse Number
Flavell, S. W., Cowan, C. W., Kim, T.-K., Greer, P. L., Lin, Y., Paradis, S., Griffith, E. C., Hu, L. S., Chen, C., & Greenberg, M. E. (2006) · Science · doi:10.1126/science.1122511 · Cited by 573 · see citing works
Self-citationTranscribed enhancers lead waves of coordinated transcription in transitioning mammalian cells
Arner, E., Daub, C. O., Vitting‐Seerup, K., Andersson, R., Lilje, B., Drabløs, F., Lennartsson, A., Rönnerblad, M., Hrydziuszko, O., Vitezic, M., et al. (2015) · Science · doi:10.1126/science.1259418 · Cited by 570 · see citing works
Regulatory Sequence Analysis Tools
van Helden, J. (2003) · Nucleic Acids Research · doi:10.1093/nar/gkg567 · Cited by 545 · see citing works
Bartel, D. P., Sheng, M., Lau, L. F., & Greenberg, M. E. (1989) · Genes & Development · doi:10.1101/gad.3.3.304 · Cited by 491 · see citing works
Convergence of Developmental and Oncogenic Signaling Pathways at Transcriptional Super-Enhancers
Hnisz, D., Schuijers, J., Lin, C. Y., Weintraub, A. S., Abraham, B. J., Lee, T. I., Bradner, J. E., & Young, R. A. (2015) · Molecular Cell · doi:10.1016/j.molcel.2015.02.014 · Cited by 476 · see citing works
Enhancer RNA Facilitates NELF Release from Immediate Early Genes
Schaukowitch, K., Joo, J., Liu, X., Watts, J. K., Martinez, C., & Kim, T.-K. (2014) · Molecular Cell · doi:10.1016/j.molcel.2014.08.023 · Cited by 445 · see citing works
Self-citationFlavell, S. W., Kim, T.-K., Gray, J. M., Harmin, D. A., Hemberg, M., Hong, E. J., Markenscoff-Papadimitriou, E., Bear, D. M., & Greenberg, M. E. (2008) · Neuron · doi:10.1016/j.neuron.2008.11.029 · Cited by 440 · see citing works
Self-citationA Switch Between Topological Domains Underlies HoxD Genes Collinearity in Mouse Limbs
Andrey, G., Montavon, T., Mascrez, B., Gonzãlez, F., Noordermeer, D., Leleu, M., Trono, D., Spitz, F., & Duboule, D. (2013) · Science · doi:10.1126/science.1234167 · Cited by 409 · see citing works
Sheng, M., Dougan, S. T., McFadden, G., & Greenberg, M. E. (1988) · Molecular and Cellular Biology · doi:10.1128/mcb.8.7.2787 · Cited by 392 · see citing works
Fleischmann, A., Hvalby, Ø., Jensen, V., Strekalova, T. V., Zacher, C., Layer, L. E., Kvello, A., Reschke, M., Spanagel, R., Sprengel, R., et al. (2003) · Journal of Neuroscience · doi:10.1523/jneurosci.23-27-09116.2003 · Cited by 382 · see citing works
Rapid and Pervasive Changes in Genome-wide Enhancer Usage during Mammalian Development
Nord, A. S., Blow, M. J., Attanasio, C., Akiyama, J. A., Holt, A., Hosseini, R., Phouanenavong, S., Plajzer-Frick, I., Shoukry, M., Afzal, V., et al. (2013) · Cell · doi:10.1016/j.cell.2013.11.033 · Cited by 375 · see citing works
H3K4 tri‐methylation provides an epigenetic signature of active enhancers
Pękowska, A., Benoukraf, T., Cabeza, J. Z., Belhocine, M., Koch, F., Holota, H., Imbert, J., Andrau, J., Ferrier, P., & Spicuglia, S. (2011) · The EMBO Journal · doi:10.1038/emboj.2011.295 · Cited by 365 · see citing works
The three 'C' s of chromosome conformation capture: controls, controls, controls
Dekker, J. (2005) · Nature Methods · doi:10.1038/nmeth823 · Cited by 347 · see citing works
Transcription initiation platforms and GTF recruitment at tissue-specific enhancers and promoters
Koch, F., Fenouil, R., Gut, M., Cauchy, P., Albert, T., Cabeza, J. Z., Spicuglia, S., de la Chapelle, A. L., Heidemann, M., Hintermair, C., et al. (2011) · Nature Structural & Molecular Biology · doi:10.1038/nsmb.2085 · Cited by 333 · see citing works
Architectural and Functional Commonalities between Enhancers and Promoters
Kim, T.-K., & Shiekhattar, R. (2015) · Cell · doi:10.1016/j.cell.2015.08.008 · Cited by 331 · see citing works
Self-citationNpas4 Regulates a Transcriptional Program in CA3 Required for Contextual Memory Formation
Ramamoorthi, K., Fropf, R., Belfort, G. M., Fitzmaurice, H. L., McKinney, R. M., Neve, R. L., Otto, T., & Lin, Y. (2011) · Science · doi:10.1126/science.1208049 · Cited by 295 · see citing works
Frey, U., Frey, S., Schollmeier, F., & Krug, M. (1996) · The Journal of Physiology · doi:10.1113/jphysiol.1996.sp021179 · Cited by 273 · see citing works
Genome-wide identification and characterization of functional neuronal activity–dependent enhancers
Malik, A. N., Vierbuchen, T., Hemberg, M., Rubin, A. A., Ling, E., Couch, C. H., Stroud, H., Spiegel, I., Farh, K. K., Harmin, D. A., et al. (2014) · Nature Neuroscience · doi:10.1038/nn.3808 · Cited by 267 · see citing works
Alteration of Neuronal Firing Properties afterIn VivoExperience in a FosGFP Transgenic Mouse
Barth, A. L., Gerkin, R. C., & Dean, K. L. (2004) · Journal of Neuroscience · doi:10.1523/jneurosci.4737-03.2004 · Cited by 255 · see citing works
RSAT 2011: regulatory sequence analysis tools
Thomas‐Chollier, M., Defrance, M., Medina-Rivera, A., Sand, O., Herrmann, C., Thieffry, D., & van Helden, J. (2011) · Nucleic Acids Research · doi:10.1093/nar/gkr377 · Cited by 228 · see citing works
Mechanisms of specificity in neuronal activity-regulated gene transcription
Lyons, M. R., & West, A. E. (2011) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2011.05.003 · Cited by 199 · see citing works
Dynamic O-GlcNAc modification regulates CREB-mediated gene expression and memory formation
Rexach, J. E., Clark, P. M., Mason, D. E., Neve, R. L., Peters, E. C., & Hsieh‐Wilson, L. C. (2012) · Nature Chemical Biology · doi:10.1038/nchembio.770 · Cited by 199 · see citing works
A new era for functional labeling of neurons: activity-dependent promoters have come of age
Kawashima, T., Okuno, H., & Bito, H. (2014) · Frontiers in Neural Circuits · doi:10.3389/fncir.2014.00037 · Cited by 165 · see citing works
Lamprecht, R., & Dudai, Y. (1996) · Learning & Memory · doi:10.1101/lm.3.1.31 · Cited by 149 · see citing works
Misra, R., Bonni, A., Miranti, C. K., Rivera, V. M., Sheng, M., & Greenberg, M. E. (1994) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)47276-6 · Cited by 148 · see citing works
Mechanisms of transcriptional precision in animal development
Lagha, M., Bothma, J. P., & Levine, M. (2012) · Trends in Genetics · doi:10.1016/j.tig.2012.03.006 · Cited by 145 · see citing works
Tissue-Specific RNA Expression Marks Distant-Acting Developmental Enhancers
Wu, H., Nord, A. S., Akiyama, J. A., Shoukry, M. I., Afzal, V., Rubin, E. M., Pennacchio, L. A., & Visel, A. (2014) · PLoS Genetics · doi:10.1371/journal.pgen.1004610 · Cited by 125 · see citing works
Sheng, M., Dougan, S. T., McFadden, G., & Greenberg, M. E. (1988) · Molecular and Cellular Biology · doi:10.1128/mcb.8.7.2787-2796.1988 · Cited by 87 · see citing works
Schwarzer, W., & Spitz, F. (2014) · Current Opinion in Genetics & Development · doi:10.1016/j.gde.2014.03.014 · Cited by 49 · see citing works
oligodeoxynucleotides to c-fos are amnestic for passive avoidance in the chick
Mileusnić, R., Anokhin, K. V., & Rose, S. P. R. (1996) · Neuroreport · doi:10.1097/00001756-199605170-00010 · Cited by 48 · see citing works
Pereira, A. H. M., Clemente, C. F. M. Z., Cardoso, A. C., Theizen, T. H., Rocco, S. A., Judice, C. C., Guido, M. C., Pascoal, V., Lopes‐Cendes, Í., Matos‐Souza, J. R., et al. (2009) · PLoS ONE · doi:10.1371/journal.pone.0008472 · Cited by 45 · see citing works
Lpd depletion reveals that SRF specifies radial versus tangential migration of pyramidal neurons
Pinheiro, E. M., Xie, Z., Norovich, A. L., Vidaki, M., Tsai, L., & Gertler, F. B. (2011) · Nature Cell Biology · doi:10.1038/ncb2292 · Cited by 40 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Three-dimensional intact-tissue sequencing of single-cell transcriptional states
Wang, X., Allen, W. E., Wright, M. A., Sylwestrak, E. L., Samusik, N., Vesuna, S., Evans, K., Liu, C., Ramakrishnan, C., Liu, J., et al. (2018) · Science · doi:10.1126/science.aat5691 · Cited by 1,620 · see citing works
Different Neuronal Activity Patterns Induce Different Gene Expression Programs
Tyssowski, K. M., DeStefino, N. R., Cho, J.-H., Dunn, C. J., Poston, R. G., Carty, C. E., Jones, R. D., Chang, S. M., Romeo, P., Wurzelmann, M. K., et al. (2018) · Neuron · doi:10.1016/j.neuron.2018.04.001 · Cited by 390 · see citing works
Li, P., Marshall, L., Oh, G., Jakubowski, J. L., Groot, D., He, Y., Wang, T., Petronis, A., & Labrie, V. (2019) · Nature Communications · doi:10.1038/s41467-019-10101-7 · Cited by 234 · see citing works
Marco, A., Meharena, H. S., Dileep, V., Raju, R. M., Davila-Velderrain, J., Zhang, A. L., Adaikkan, C., Young, J. Z., Gao, F., Kellis, M., et al. (2020) · Nature Neuroscience · doi:10.1038/s41593-020-00717-0 · Cited by 159 · see citing works
Beagan, J. A., Pastuzyn, E. D., Fernandez, L. R., Guo, M. H., Feng, K., Titus, K. R., Chandrashekar, H., Shepherd, J. D., & Phillips-Cremins, J. E. (2020) · Nature Neuroscience · doi:10.1038/s41593-020-0634-6 · Cited by 143 · see citing works
Saul, M. C., Seward, C. H., Troy, J. M., Zhang, H., Sloofman, L. G., Lu, X., Weisner, P. A., Caetano-Anolles, D., Sun, H., Zhao, S. D., et al. (2017) · Genome Research · doi:10.1101/gr.214221.116 · Cited by 46 · see citing works
Duttke, S. H., Montilla-Perez, P., Chang, M. W., Li, H., Chen, H., Carrette, L. L. G., Guglielmo, G. D., George, O., Palmer, A. A., Benner, C., et al. (2022) · Frontiers in Neuroscience · doi:10.3389/fnins.2022.858427 · Cited by 26 · see citing works
Hamilton, P. J., Lim, C. J., Nestler, E. J., & Heller, E. A. (2018) · Methods in Molecular Biology · doi:10.1007/978-1-4939-7774-1_5 · Cited by 28 · see citing works
Three-dimensional chromatin organization in brain function and dysfunction
Dileep, V., & Tsai, L.-H. (2021) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2021.04.006 · Cited by 14 · see citing works
Chimeric brain models to study human glial-neuronal and macroglial-microglial interactions
Jin, M., Ma, Z., Zhang, H., Dang, R., Papetti, A. V., Stillitano, A. C., Zou, L., Goldman, S. A., & Jiang, P. (2026) · Cell Reports · doi:10.1016/j.celrep.2025.116794 · Cited by 6 · see citing works
- Authors
- Joo, J.-Y., Schaukowitch, K., Farbiak, L., Kilaru, G., & Kim, T.-K.
- Affiliations
- The University of Texas Southwestern Medical Center (US)
- Corresponding author
- Kim, Tae-Kyung
- Venue
- Nature Neuroscience
- Published
- 2015-11-23
- Volume
- 19
- Issue
- 1
- Pages
- 75-83
- ISSN
- 1097-6256 (ISSN-L)
- 1546-1726
- PMC
- PMC4696896
- OpenAlex
- W2177873964
- Cited by
- 271
- References
- 55
- Citations by year
- 2026: 21 · 2025: 28 · 2024: 39 · 2023: 29 · 2022: 30 · 2021: 27 · 2020: 19 · 2019: 24 · 2018: 23 · 2017: 16 · 2016: 15
- FWCI
- 7.81
- Type
- journal article
- Language
- en
- Update notices
- erratum (2016-03-29)
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Open Access System for Information Sharing (Pohang University of Science and Technology) (submittedVersion)
- Funders
- National Science Foundation
- Corporación de Fomento de la Producción
- National Institute of Neurological Disorders and Stroke (R01NS085418)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Keywords
- c-fos, enhancers, neuronal activity, transcriptional regulation, membrane depolarization, brain-derived neurotrophic factor, forskolin, transcription factors, neuroplasticity, activity-dependent gene expression
- MeSH terms
- Animals, Brain, Embryo, Mammalian, Enhancer Elements, Genetic, Neuronal Plasticity, Neurons, Promoter Regions, Genetic, RNA, Messenger, Transcription, Genetic, Gene Expression, Genes, fos, Brain-Derived Neurotrophic Factor, Epigenesis, Genetic, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
