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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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“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]
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“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]
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“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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BackgroundMethodLandscape of cohesin-mediated chromatin loops in the human genome
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“[15-60] Solyc08g062437 Solyc08g062437 Mo f Mo f family P-value”
BackgroundELF3, ELF5, EHF and SPDEF Transcription Factors in Tissue Homeostasis and Cancer
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“As EHF was the ESE factor found to have the highest lineage-specific expression in stratified epithelia, its role in keratinocyte differentiation was directly investigated by knockdown in organotypic human epidermal tissue, revealing that EHF regulates ~400 genes in this tissue including several associated with kerati…”
BackgroundLong-range interactions between proximal and distal regulatory regions in maize
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“During differentiation, acquisition of H3K27ac at enhancers is associated with the formation of enhancer-promoter interactions and induction of their target genes (Wang et al., 2016; Rubin et al., 2017).”
BackgroundMyoD is a 3D genome structure organizer for muscle cell identity
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Self-citationChromatin conformation remains stable upon extensive transcriptional changes driven by heat shock
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“Although it has been shown that regulatory contacts are newly formed or strengthened while cells are undergoing transcriptional changes (45–47), there is also evidence of preestablished enhancer–promoter interactions during stimuli activation, differentiation, development, and stress (31, 45, 48, 49).”
BackgroundDynamics of the 4D Genome during in Vivo Lineage Specification and Differentiation
Oudelaar, A. M., Beagrie, R. A., Gosden, M., de Ornellas, S., Georgiades, E., Kerry, J., Hidalgo, D., Carrelha, J., Shivalingam, A., El-Sagheer, A. H., et al. (2020) · Nature Communications · doi:10.1038/s41467-020-16598-7 · Cited by 119
RNA polymerase II dynamics shape enhancer–promoter interactions
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“In summary, we identified putative target genes for the majority of enhancers and found that many genes can be paired with multiple enhancers, in line with previous reports (Beagrie et al., 2017; Rubin et al., 2017).”
ResultPromoter Capture Hi-C: High-resolution, Genome-wide Profiling of Promoter Interactions
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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.”
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MethodForces driving the three‐dimensional folding of eukaryotic genomes
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“…, 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
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“Nonetheless, a significant minority of enhancers in human ESCs also show pre-existing “permissive” promoter contacts prior to activation [141, 394].”
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BackgroundCore transcription regulatory circuitry orchestrates corneal epithelial homeostasis
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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.”
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BackgroundMethodChromatin Conformation in Development and Disease
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BackgroundInfluentialAn RNA-centric view of transcription and genome organization
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Self-citationFoxP3 associates with enhancer-promoter loops to regulate Treg-specific gene expressionPreprint
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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, A. J., Guerrero, G., Furlan-Magaril, M., & Recillas-Targa, F. (2019) · Nature Communications · doi:10.1038/s41467-020-14651-z · Cited by 36
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 45
“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
“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
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 41
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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 39
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 38
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 40
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
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 42
“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
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
“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
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 38
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“…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
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“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
“…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
“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 34
Jin, 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 33
“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
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
Genome organization at different scales: nature, formation and function
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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 35
Laverré, A., Tannier, É., & Necşulea, A. (2021) · Genome Research · doi:10.1101/gr.275901.121 · Cited by 30
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Three-dimensional genome landscape of primary human cancers
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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
“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., Sikorska, N., Pancaldi, V., & Sexton, T. (2018) · Genome Biology · doi:10.1186/s13059-019-1706-3 · Cited by 27
“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. M., Nagarajan, P., & Ge, Y. (2019) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2019.107448 · Cited by 30
“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…”
BackgroundInfluentialEnhancer RNAs: Insights Into Their Biological Role
de Lara, J. C.-F., Arzate‐Mejía, R. G., & Targa, F. R. (2019) · Epigenetics Insights · doi:10.1177/2516865719846093 · Cited by 28
Metadata
- 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
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