Lineage-specific dynamic and pre-established enhancer-promoter contacts cooperate in terminal differentiation
Open accessAbstract
Chromosome conformation is an important feature of metazoan gene regulation; however, enhancer-promoter contact remodeling during cellular differentiation remains poorly understood. To address this, genome-wide promoter capture Hi-C (CHi-C) was performed during epidermal differentiation. Two classes of enhancer-promoter contacts associated with differentiation-induced genes were identified. The first class ('gained') increased in contact strength during differentiation in concert with enhancer acquisition of the H3K27ac activation mark. The second class ('stable') were pre-established in undifferentiated cells, with enhancers constitutively marked by H3K27ac. The stable class was associated with the canonical conformation regulator cohesin, whereas the gained class was not, implying distinct mechanisms of contact formation and regulation. Analysis of stable enhancers identified a new, essential role for a constitutively expressed, lineage-restricted ETS-family transcription factor, EHF, in epidermal differentiation. Furthermore, neither class of contacts was observed in pluripotent cells, suggesting that lineage-specific chromatin structure is established in tissue progenitor cells and is further remodeled in terminal differentiation.
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A significant minority of enhancers in human ESCs show pre-existing "permissive" promoter contacts prior to activation.
“Nonetheless, a significant minority of enhancers in human ESCs also show pre-existing “permissive” promoter contacts prior to activation [141, 394].”
From Transcriptional enhancers and their communication with gene promoters (2021) · cites this paper as [394]
The Abstract says the pre-established enhancer–promoter contacts studied were present in epidermal progenitor cells but not in embryonic stem cells. Its analysis of hESC promoter-contact data likewise reports reduced contact signal relative to keratinocytes. The paper places these pre-established contacts after pluripotency, not in hESCs. (LLM, conf=0.88)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measuredIn mammalian differentiation models, extensive remodelling of enhancer-promoter contacts is typically observed consistently with enhancer activation.
“In mammalian differentiation models, in contrast, extensive remodelling of enhancer–promoter contacts is typically observed consistently with enhancer activation [141, 394–397].”
From Transcriptional enhancers and their communication with gene promoters (2021) · cites this paper as [394]
The indexed passages (section labeled Abstract; no page given) report that enhancer–promoter contacts gained strength alongside enhancer H3K27ac activation during epidermal differentiation. But the paper studies this differentiation model, not what is typically observed across mammalian models, and it also reports that 65% of differentiation-induced genes had exclusively stable, pre-established contacts. The broader claim of typical extensive remodelling therefore overstates this source. (LLM, conf=0.86)
Experimental — accuracy not yet measuredEHF is an ETS factor implicated in controlling epidermal differentiation.
“As a Module 3 regulator, we chose EHF, an ETS factor implicated in controlling epidermal differentiation (Rubin et al., 2017).”
From Coupled Single-Cell CRISPR Screening and Epigenomic Profiling Reveals Causal Gene Regulatory Networks (2019) · cites this paper as Rubin et al., 2017
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Self-citationOncogenic Notch Promotes Long-Range Regulatory Interactions within Hyperconnected 3D Cliques
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Self-citationMapping effector genes at lupus GWAS loci using promoter Capture-C in follicular helper T cells
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Self-citationIncreased enhancer–promoter interactions during developmental enhancer activation in mammals
Chen, Z., Snetkova, V., Bower, G., Jacinto, S. H., Clock, B., Dizehchi, A., Barozzi, I., Mannion, B. J., Alcaina‐Caro, A., López-Rı́os, J., et al. (2024) · Nature Genetics · doi:10.1038/s41588-024-01681-2 · Cited by 84 · see citing works
“Similar stable loops have been reported for other mammalian loci 17,20,21,41 , where they likely provide an additional level of robustness to maintain stable levels of gene expression during development 41 .”
Single-Cell Multi-omics: An Engine for New Quantitative Models of Gene Regulation
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“…regulated remains unclear and may involve ubiquitously expressed transcription factors (TFs) for permissive interactions, as suggested for CTCF (CCCTC-binding factor)/cohesin 14 , while lineage-or stimulus-specific TFs are associated with both instructive 22,26,27 and permissive 22 interactions.”
Jia, Z., Li, J., Ge, X., Wu, Y., Guo, Y., & Wu, Q. (2020) · Genome biology · doi:10.1186/s13059-020-01984-7 · Cited by 81 · see citing works
“We analyzed 207,663 enhancerpromoter contacts of the capture Hi-C data for the genome-wide relationship between insulators, enhancers, and promoters [46] .”
MethodForces driving the three‐dimensional folding of eukaryotic genomes
Rada-Iglesias, Á., Grosveld, F. G., & Papantonis, A. (2018) · Molecular Systems Biology · doi:10.15252/msb.20188214 · Cited by 81 · see citing works
“…, 2016), during macrophage development (mediated by AP-1; Phanstiel et al , 2017), differentiation of the epidermis (mediated by ETS family factors; Rubin et al , 2017), upon adipogenesis (via both activators like C/EBP and co-repressors like NuRD; Siersbæk et al , 2017), or by the homotypic…”
Transcriptional reprogramming at the intersection of the heat shock response and proteostasis
Pessa, J. C., Joutsen, J., & Sistonen, L. (2023) · Molecular Cell · doi:10.1016/j.molcel.2023.11.024 · Cited by 82 · see citing works
Transcriptional enhancers and their communication with gene promoters
Ray-Jones, H., & Spivakov, M. (2021) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-021-03903-w · Cited by 81 · see citing works
“Nonetheless, a significant minority of enhancers in human ESCs also show pre-existing “permissive” promoter contacts prior to activation [141, 394].”
BackgroundSelf-citationTranscriptional control by enhancers and enhancer RNAs
Lewis, M. W., Shen, L., & Franco, H. L. (2019) · Transcription · doi:10.1080/21541264.2019.1695492 · Cited by 78 · see citing works
“[139] Rubin AJ, Barajas BC, Furlan-Magaril M, et al.”
The dynamic, combinatorial cis-regulatory lexicon of epidermal differentiation
Kim, D. S., Risca, V. I., Reynolds, D. L., Chappell, J., Rubin, A. J., Jung, N., Donohue, L. K. H., Lopez-Pajares, V., Kathiria, A. S., Shi, M., et al. (2021) · Nature Genetics · doi:10.1038/s41588-021-00947-3 · Cited by 74 · see citing works
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Understanding the 3D genome: Emerging impacts on human disease
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Transcription-dependent cohesin repositioning rewires chromatin loops in cellular senescence
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Self-citationMechanisms of Enhancer-Promoter Interactions in Higher Eukaryotes
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“Interactions between enhancers and promoters can be formed both before and simultaneous with transcription activation [44,47,48].”
BackgroundThree-dimensional chromatin in disease: What holds us together and what drives us apart?
Ibrahim, D. M., & Mundlos, S. (2020) · Current Opinion in Cell Biology · doi:10.1016/j.ceb.2020.01.003 · Cited by 66 · see citing works
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“TAD boundaries are overall well conserved along the linear genome between cell types [52] and during differentiation [55,56], suggesting that TADs constitute structural entities of the genome.”
BackgroundRuss, B. E., Olshansky, M., Li, J., Nguyen, M. L. T., Gearing, L. J., Nguyen, T. H. O., Olson, M. R., McQuilton, H. A., Nüssing, S., Khoury, G., et al. (2017) · Cell Reports · doi:10.1016/j.celrep.2017.11.097 · Cited by 65 · see citing works
“It has recently been determined that preconfiguration of chromatin structures is important for enabling cellular differentiation (Rubin et al., 2017).”
BackgroundCore transcription regulatory circuitry orchestrates corneal epithelial homeostasis
Li, M., Huang, H., Li, L., He, C., Zhu, L., Guo, H., Wang, L., Liu, J., Wu, S., Liu, J., et al. (2021) · Nature Communications · doi:10.1038/s41467-020-20713-z · Cited by 61 · see citing works
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“Further investigation into the differential enhancer-promoter contacts induced by MYCi975 using promoter capture Hi-C ( 46 , 47 ) may reveal the role of enhancer-bound MYC/ MAX heterodimers in MYCi975-sensitive gene regulation.”
Liu, R., Liu, R., Zheng, M., Feng, F., Liu, D., Guo, Y., Zhao, G., & Wen, J. (2020) · Journal of Animal Science and Biotechnology/Journal of animal science and biotechnology · doi:10.1186/s40104-020-00469-8 · Cited by 60 · see citing works
Genetics in Atopic Dermatitis: Historical Perspective and Future Prospects
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“Importantly, since the 3D interactions are cell-type as well as cell-state-specific, Hi-C analysis has been applied to differentiating keratinocytes, to characterise spacial control of promotor-enhancer interactions likely to be of relevance to AD (56, 67).”
BackgroundMethodChromatin Conformation in Development and Disease
Boltsis, I., Grosveld, F. G., Giraud, G., & Kolovos, P. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.723859 · Cited by 56 · see citing works
“Some promoter–enhancer interactions could also be established only by transcription factors without the involvement of cohesin (Rubin et al., 2017).”
BackgroundInfluentialAn RNA-centric view of transcription and genome organization
Henninger, J. E., & Young, R. A. (2024) · Molecular Cell · doi:10.1016/j.molcel.2024.08.021 · Cited by 56 · see citing works
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3D chromatin architecture and epigenetic regulation in cancer stem cells
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Nuclear pores in genome architecture and enhancer function
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RNA proximity sequencing reveals the spatial organization of the transcriptome in the nucleus
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Self-citationFoxP3 associates with enhancer-promoter loops to regulate Treg-specific gene expressionPreprint
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Random allelic expression in the adult human body
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Self-citationIn situ dissection of domain boundaries affect genome topology and gene transcription in Drosophila
Arzate‐Mejía, R. G., Cerecedo-Castillo, Á. J., Guerrero, G., Furlan-Magaril, M., & Targa, F. R. (2020) · Nature Communications · doi:10.1038/s41467-020-14651-z · Cited by 44 · see citing works
Self-citationDynamic 3D Chromatin Reorganization during Establishment and Maintenance of Pluripotency
Pelham‐Webb, B., Murphy, D., & Apostolou, E. (2020) · Stem Cell Reports · doi:10.1016/j.stemcr.2020.10.012 · Cited by 43 · see citing works
“This suggests that developmentally relevant chromatin structures may be already established in PSCs, as shown before (Cruz-Molina et al., 2017; Rubin et al., 2017; Schoenfelder et al., 2015a), but also selectively maintained during mitosis to enable rapid G1 activation and differentiation uponproper stimulation.”
BackgroundMiroshnikova, Y. A., Cohen, I., Ezhkova, E., & Wickström, S. A. (2019) · Current Opinion in Genetics & Development · doi:10.1016/j.gde.2019.04.014 · Cited by 44 · see citing works
“A genome-wide promoter capture Hi-C method coupled with chromatin immunoprecipitation (ChIP) analysis of H3K27ac uncovered two classes of enhancer-promoter contacts associated with epidermal differentiation genes [24].”
BackgroundMethodInfluentialEpigenetic control in skin development, homeostasis and injury repair
Kang, S., Chovatiya, G. L., & Tumbar, T. (2019) · Experimental Dermatology · doi:10.1111/exd.13872 · Cited by 43 · see citing works
Chromatin interactome mapping at 139 independent breast cancer risk signals
Beesley, J., Sivakumaran, H., Marjaneh, M. M., Lima, L. G., Hillman, K. M., Kaufmann, S., Tuano, N., Hussein, N., Ham, S., Mukhopadhyay, P., et al. (2020) · Genome biology · doi:10.1186/s13059-019-1877-y · Cited by 43 · see citing works
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A chromosomal loop anchor mediates bacterial genome organization
Dugar, G., Hofmann, A., Heermann, D. W., & Hamoen, L. W. (2022) · Nature Genetics · doi:10.1038/s41588-021-00988-8 · Cited by 36 · see citing works
p63 cooperates with CTCF to modulate chromatin architecture in skin keratinocytes
Qu, J., Yi, G., & Zhou, H. (2019) · Epigenetics & Chromatin · doi:10.1186/s13072-019-0280-y · Cited by 37 · see citing works
Skeletal muscle enhancer interactions identify genes controlling whole-body metabolism
Williams, K., Ingerslev, L. R., Bork‐Jensen, J., Wohlwend, M., Hansen, A. N., Small, L., Ribel‐Madsen, R., Astrup, A. V., Pedersen, O. B., Auwerx, J. H., et al. (2020) · Nature Communications · doi:10.1038/s41467-020-16537-6 · Cited by 39 · see citing works
Combinatorial Action of Temporally Segregated Transcription Factors
Charest, J., Daniele, T., Wang, J., Bykov, A., Mandlbauer, A., Asparuhova, M., Roehsner, J., Gutiérrez‐Pérez, P., & Cochella, L. (2020) · Developmental Cell · doi:10.1016/j.devcel.2020.09.002 · Cited by 37 · see citing works
Enhancer DNA methylation in acute myeloid leukemia and myelodysplastic syndromes
Benetatos, L., & Vartholomatos, G. (2018) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-018-2783-2 · Cited by 40 · see citing works
“These enhancer–promoter interactions occur within topological association domains (TADs), established after pluripotency but before induction of terminal differentiation [28].”
BackgroundA transcription factor network represses CFTR gene expression in airway epithelial cells
Mutolo, M. J., Leir, S., Fossum, S. L., Browne, J. A., & Harris, A. (2018) · Biochemical Journal · doi:10.1042/bcj20180044 · Cited by 38 · see citing works
Chromatin Looping Links Target Genes with Genetic Risk Loci for Dermatological Traits
Shi, C., Ray-Jones, H., Ding, J., Duffus, K., Fu, Y., Gaddi, V. P., Gough, O., Hankinson, J., Martin, P., McGovern, A., et al. (2021) · Journal of Investigative Dermatology · doi:10.1016/j.jid.2021.01.015 · Cited by 32 · see citing works
“Although these techniques are very promising, there has been a lack of studies in disease-relevant cell types, and as recently evidenced, both chromatin interactions and gene regulation are cell type and stimulation specific (Burren et al., 2017; Dixon et al., 2012; Hansen et al., 2018; Mumbach et al., 2017; Rao et al…”
BackgroundThe global and promoter-centric 3D genome organization temporally resolved during a circadian cycle
Furlan-Magaril, M., Ando-Kuri, M., Arzate-Mejía, R. G., Morf, J., Cairns, J., Román-Figueroa, A., Tenorio-Hernández, L., Poot-Hernández, A. C., Andrews, S., Várnai, C., et al. (2021) · Genome Biology · doi:10.1186/s13059-021-02374-3 · Cited by 39 · see citing works
Self-citationSahlén, P., Spalinskas, R., Asad, S., Mahapatra, K. D., Höjer, P., Anil, A., Eisfeldt, J., Srivastava, A., Nikamo, P., Mukherjee, A., et al. (2020) · Journal of Allergy and Clinical Immunology · doi:10.1016/j.jaci.2020.09.035 · Cited by 37 · see citing works
Yun, H.-Y., Narayan, N., Vohra, S., Giotopoulos, G., Mupo, A., Madrigal, P., Sasca, D., Lara-Astiaso, D., Horton, S., Agrawal-Singh, S., et al. (2021) · Nature Genetics · doi:10.1038/s41588-021-00925-9 · Cited by 14 · see citing works
“…11% of all high-confidence interactions were significantly differential (gained or lost) in SM or DM HSPC, based on stringent alterations of the ranking of CHiCAGO scores 29,30 (Figure 4g), with more interactions lost than newly formed in the mutant states (Figure 4h and Supplementary Table 8).”
Revisiting 3D chromatin architecture in cancer development and progression
Feng, Y., & Pauklin, S. (2020) · Nucleic Acids Research · doi:10.1093/nar/gkaa747 · Cited by 36 · see citing works
“A recent report showed that there are two classes of enhancer–promoter interactions in progenitor and differentiating primary human epidermal keratinocytes (128).”
BackgroundDetecting chromosomal interactions in Capture Hi-C data with CHiCAGO and companion tools
Freire-Pritchett, P., Ray-Jones, H., Rosa, M. D., Eijsbouts, C., Orchard, W. R., Wingett, S., Wallace, C., Cairns, J. M., Spivakov, M., & Malysheva, V. (2021) · Nature Protocols · doi:10.1038/s41596-021-00567-5 · Cited by 34 · see citing works
“…high-throughput sequencing (ATAC-seq) and RNA-seq has provided insights, for example, into the rewiring of promoter – enhancer contacts upon the differentiation of embryonic stem (ES) cells 23 – 25 , adipocytes 26 and keratinocytes 27 , as well as upon cohesin depletion in a human cell line 28 .”
BackgroundSelf-citationp63 Is a Promising Marker in the Diagnosis of Unusual Skin Cancer
Smirnov, A., Anemona, L., Novelli, F., Piro, M. C., Annicchiarico‐Petruzzelli, M., Melino, G., & Candi, E. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20225781 · Cited by 35 · see citing works
“These might interact with the promoter regions of target genes to allow their transcription during differentiation [46].”
BackgroundSnetkova, V., & Skok, J. A. (2018) · Epigenomics · doi:10.2217/epi-2017-0157 · Cited by 32 · see citing works
Promoter Capture Hi-C: High-resolution, Genome-wide Profiling of Promoter Interactions
Schoenfelder, S., Javierre, B. M., Furlan-Magaril, M., Wingett, S., & Fraser, P. (2018) · Journal of Visualized Experiments · doi:10.3791/57320-v · Cited by 34 · see citing works
Self-citationJin, L., Chen, Y., Muzaffar, S., Li, C., Mier-Aguilar, C. A., Khan, J., Kashyap, M. P., Liu, S., Srivastava, R. K., Deshane, J. S., et al. (2023) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2315096120 · Cited by 32 · see citing works
“Lineage - specific chromatin structure is established during somatic stem cell commitment and is further remodeled in terminal differentiation (24).”
BackgroundParkinson's disease genetic risk in a midbrain neuronal cell line.
Pierce, S. E., Tyson, T. A., Booms, A., Prahl, J. D., & Coetzee, G. (2018) · Neurobiology of Disease · doi:10.1016/j.nbd.2018.02.007 · Cited by 34 · see citing works
Cohesin-mediated 3D contacts tune enhancer-promoter regulationPreprint
Guckelberger, P., Doughty, B. R., Munson, G., Rao, S. S. P., Tan, Y., Cai, X. S., Fulco, C. P., Nasser, J., Mualim, K. S., Bergman, D. T., et al. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.07.12.603288 · Cited by 33 · see citing works
Genome organization at different scales: nature, formation and function
Serizay, J., & Ahringer, J. (2018) · Current Opinion in Cell Biology · doi:10.1016/j.ceb.2018.03.009 · Cited by 32 · see citing works
CTCF depletion decouples enhancer-mediated gene activation from chromatin hub formation
Karpińska, M. A., Zhu, Y., Ghazvini, Z. F., Ramasamy, S., Barbieri, M., Cao, T. B. N., Varahram, N., Aljahani, A., Lidschreiber, M., Papantonis, A., et al. (2025) · Nature Structural & Molecular Biology · doi:10.1038/s41594-025-01555-z · Cited by 34 · see citing works
Laverré, A., Tannier, É., & Necşulea, A. (2021) · Genome Research · doi:10.1101/gr.275901.121 · Cited by 31 · see citing works
Hao, R.-H., Guo, Y., Wang, C., Chen, F., Di, C., Dong, S., Cao, Q.-L., Guo, J., Rong, Y., Yao, S., et al. (2022) · Cell Death and Differentiation · doi:10.1038/s41418-022-01035-7 · Cited by 30 · see citing works
Three-dimensional genome landscape of primary human cancers
Yost, K. E., Zhao, Y., Hung, K. L., Zhu, K., Xu, D., Corces, M. R., Shams, S., Louie, B. H., Sarmashghi, S., Sundaram, L., et al. (2025) · Nature Genetics · doi:10.1038/s41588-025-02188-0 · Cited by 34 · see citing works
Self-citationHigh-Resolution Mapping of Multiway Enhancer-Promoter Interactions Regulating Pathogen Detection
Vangala, P., Murphy, R., Quinodoz, S. A., Gellatly, K. J., McDonel, P. E., Guttman, M., & Garber, M. G. (2020) · Molecular Cell · doi:10.1016/j.molcel.2020.09.005 · Cited by 29 · see citing works
“In fact, as others have observed in different contexts (Rubin et al., 2017; Ghavi-Helm et al., 2014; Jin et al., 2013), only a small fraction (10%) of interactions have detectable changes upon LPS stimulation (Figure 6A, top; Figures S2E–S2K; STAR Methods).”
BackgroundZouari, Y. B., Molitor, A. M., Sikorska, N., Pancaldi, V., & Sexton, T. (2019) · Genome biology · doi:10.1186/s13059-019-1706-3 · Cited by 28 · see citing works
“For example, promoter-centered interactomes have already been used to assign 50 epigenomic status and follow enhancer looping dynamics throughout development, as well as 51 to characterize disease-linked intergenic sequence polymorphisms [13-17].”
MethodUnraveling cancer lineage drivers in squamous cell carcinomas
Guan, Y., Wang, G., Fails, D., Nagarajan, P., & Ge, Y. (2019) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2019.107448 · Cited by 29 · see citing works
“Mechanistically, TP63 directly targets key squamous lineage genes, for example the keratin gene KRT14 (Candi et al., 2006), a tetraspan membrane protein and cell adhesion regulator Perp (Ihrie et al., 2005), and an extracellular matrix gene Fras1 (Koster et al., 2007), all characteristic of stratified epithelia (Figur…”
BackgroundInfluential
- Authors
- Rubin, A. J., Barajas, B. C., Furlan-Magaril, M., Lopez-Pajares, V., Mumbach, M. R., Howard, I., Kim, D. S., Boxer, L. D., Cairns, J., Spivakov, M., Wingett, S. W., Shi, M., Zhao, Z., Greenleaf, W. J., Kundaje, A., Snyder, M., Chang, H. Y., Fraser, P., & Khavari, P. A.
- Affiliations
- Stanford Medicine (US)
- Babraham Institute (GB)
- Florida State University (US)
- VA Palo Alto Health Care System (US)
- Corresponding author
- Khavari, Paul A
- ORCID
- Venue
- Nature Genetics
- Published
- 2017-08-14
- Volume
- 49
- Issue
- 10
- Pages
- 1522-1528
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- PMC
- PMC5715812
- OpenAlex
- W2745773403
- Cited by
- 293
- References
- 44
- Citations by year
- 2026: 9 · 2025: 15 · 2024: 24 · 2023: 30 · 2022: 44 · 2021: 56 · 2020: 45 · 2019: 34 · 2018: 31 · 2017: 5
- FWCI
- 12.84
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Nature Genetics (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Funders
- Biotechnology and Biological Sciences Research Council (BBS/E/B/000C0405, BBS/E/B/000C0404, BB/J004480/1)
- National Heart, Lung, and Blood Institute (R01HL122887)
- National Human Genome Research Institute (U01HG007919, T32HG000044)
- National Institute of General Medical Sciences (T32GM007276)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (K01AR070895, R01AR045192)
- 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-promoter interactions, 3D genome organization, epidermal differentiation, terminal differentiation, H3K27ac, cohesin, EHF, ETS transcription factors, promoter capture Hi-C, chromatin remodeling, pluripotent cells
- MeSH terms
- Epidermal Cells, Acetylation, Calcium, Cell Differentiation, Cells, Cultured, Chromosomes, Human, Enhancer Elements, Genetic, Gene Expression Regulation, Histones, Humans, Male, Promoter Regions, Genetic, Protein Processing, Post-Translational, RNA, Transcription Factors, Keratinocytes, Gene Library, Cell Lineage, RNA Interference, Histone Code
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 ›
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