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Cited by 116Genomics and Chromatin DynamicsEpigenetics and DNA MethylationChromatin Remodeling and Cancer

Orphan CpG islands amplify poised enhancer regulatory activity and determine target gene responsiveness

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Pachano, Tomas, Sánchez-Gaya, Víctor, Ealo, Thais, Mariner-Faulí, Maria, Bleckwehl, Tore, Asenjo, Helena G., Respuela, Patricia, Cruz-Molina, Sara +5 more·2021·Nature Genetics
DOI 10.1038/s41588-021-00888-xPMC PMC7611182

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Abstract

CpG islands (CGIs) represent a widespread feature of vertebrate genomes, being associated with ~70% of all gene promoters. CGIs control transcription initiation by conferring nearby promoters with unique chromatin properties. In addition, there are thousands of distal or orphan CGIs (oCGIs) whose functional relevance is barely known. Here we show that oCGIs are an essential component of poised enhancers that augment their long-range regulatory activity and control the responsiveness of their target genes. Using a knock-in strategy in mouse embryonic stem cells, we introduced poised enhancers with or without oCGIs within topologically associating domains harboring genes with different types of promoters. Analysis of the resulting cell lines revealed that oCGIs act as tethering elements that promote the physical and functional communication between poised enhancers and distally located genes, particularly those with large CGI clusters in their promoters. Therefore, by acting as genetic determinants of gene-enhancer compatibility, CGIs can contribute to gene expression control under both physiological and potentially pathological conditions.

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  • Enhancers and promoters tend to differ in GC content, with many promoters and only a subset of enhancers containing CpG islands.

    “In terms of their sequence properties, enhancers and promoters tend to differ in GC content, with many promoters and only a subset of enhancers containing CpG islands [74, 249].”

    From Transcriptional enhancers and their communication with gene promoters (2021) · cites this paper as [249]

    The Introduction (page unavailable) says CpG islands are prevalent at vertebrate promoters. The Results, under “Genetic properties of PE-associated oCGIs” (page unavailable), report that roughly 60–80% of the poised enhancers studied lie near a CpG island and that their associated islands can have lower GC content than classically defined islands. The paper does not establish the claimed GC-content difference or CpG-island frequency for enhancers generally. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

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Authors
Pachano, T., Sánchez-Gaya, V., Ealo, T., Mariner-Faulí, M., Bleckwehl, T., Asenjo, H. G., Respuela, P., Cruz-Molina, S., Muñoz-San Martín, M., Haro, E., van IJcken, W. F. J., Landeira, D., & Rada-Iglesias, A.
Affiliations
  • Universidad de Cantabria (ES)
  • University of Cologne (DE)
  • Universidad de Granada (ES)
  • Max Planck Institute for Molecular Biomedicine (DE)
ORCID
Venue
Nature Genetics
Publisher
Springer Science and Business Media LLC
Published
2021-06-28
Volume
53
Issue
7
Pages
1036-1049
ISSN
  • 1061-4036 (ISSN-L)
  • 1546-1718
DOI
10.1038/s41588-021-00888-x
PMC
PMC7611182
OpenAlex
W3176042246
Cited by
116
References
18
Citations by year
2026: 12 · 2025: 18 · 2024: 30 · 2023: 19 · 2022: 24 · 2021: 12 · 2020: 1
FWCI
7.14
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Genetics (publishedVersion)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • EUR Research Repository (Erasmus University Rotterdam) (publishedVersion, other-oa)
  • PubMed (publishedVersion)
  • Kölner Universitäts PublikationsServer (Universität zu Köln) (publishedVersion)
  • PubMed Central (acceptedVersion)
  • EUR Research Repository (Erasmus University Rotterdam) (submittedVersion, other-oa)
  • Institutional Repository of the University of Granada (University of Granada) (submittedVersion, other-oa)
  • DIGITAL.CSIC (Spanish National Research Council (CSIC)) (submittedVersion)
  • UCrea (University of Cantabria) (submittedVersion, cc-by)
Funders
  • Ministerio de Ciencia, Innovación y Universidades (PID2019, PGC 2018)
  • Deutscher Akademischer Austauschdienst
  • Deutsche Forschungsgemeinschaft
  • Universidad de Cantabria
  • H2020 European Research Council
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
Keywords
poised enhancers, enhancer-promoter interactions, topologically associating domains, gene expression regulation, chromatin accessibility, mouse embryonic stem cells, promoter CpG islands
MeSH terms
Animals, Chromatin, Enhancer Elements, Genetic, Gene Expression Regulation, Promoter Regions, Genetic, CpG Islands, DNA Methylation, Epigenesis, Genetic, Mice, Embryonic Stem Cells, Gene Knock-In Techniques

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