Cited by 305Genomics and Chromatin DynamicsChromatin Remodeling and CancerEpigenetics and DNA Methylation

Lineage-specific dynamic and pre-established enhancer-promoter contacts cooperate in terminal differentiation

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Rubin, Adam J, Barajas, Brook C, Furlan-Magaril, Mayra, Lopez-Pajares, Vanessa, Mumbach, Maxwell R, Howard, Imani, Kim, Daniel S, Boxer, Lisa D +11 more·2017·Nature Genetics

Abstract

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)

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  • In 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 measured
  • EHF 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).”

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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
Venue
Nature Genetics
Published
2017-08-14
Volume
49
Issue
10
Pages
1522-1528
ISSN
  • 1061-4036 (ISSN-L)
  • 1546-1718
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
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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