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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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“Our measurements provide further insights into the open debate whether topology precedes transcription 44,45 .”
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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