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Cited by 25Genomics and Chromatin DynamicsGenetic Associations and EpidemiologyEpigenetics and DNA Methylation

Functional effects of variation in transcription factor binding highlight long-range gene regulation by epromoters

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Mitchelmore, Joanna, Grinberg, Nastasiya F, Wallace, Chris, Spivakov, Mikhail·2020·Nucleic Acids Research
DOI 10.1093/nar/gkaa123PMC PMC7102942

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Abstract

Identifying DNA cis-regulatory modules (CRMs) that control the expression of specific genes is crucial for deciphering the logic of transcriptional control. Natural genetic variation can point to the possible gene regulatory function of specific sequences through their allelic associations with gene expression. However, comprehensive identification of causal regulatory sequences in brute-force association testing without incorporating prior knowledge is challenging due to limited statistical power and effects of linkage disequilibrium. Sequence variants affecting transcription factor (TF) binding at CRMs have a strong potential to influence gene regulatory function, which provides a motivation for prioritizing such variants in association testing. Here, we generate an atlas of CRMs showing predicted allelic variation in TF binding affinity in human lymphoblastoid cell lines and test their association with the expression of their putative target genes inferred from Promoter Capture Hi-C and immediate linear proximity. We reveal >1300 CRM TF-binding variants associated with target gene expression, the majority of them undetected with standard association testing. A large proportion of CRMs showing associations with the expression of genes they contact in 3D localize to the promoter regions of other genes, supporting the notion of ‘epromoters’: dual-action CRMs with promoter and distal enhancer activity.

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  • Genetic variants at epromoters may affect the expression of both the proximal and distal gene, but a large proportion are associated with only the distal one.

    “In addition, whilst genetic variants at epromoters may affect the expression of both the proximal and distal gene, a large proportion are associated with only the distal one [207].”

    From Transcriptional enhancers and their communication with gene promoters (2021) · cites this paper as [207]

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Authors
Mitchelmore, J., Grinberg, N. F., Wallace, C., & Spivakov, M.
Affiliations
  • Babraham Institute (GB)
  • University of Cambridge (GB)
Corresponding author
Spivakov, Mikhail
ORCID
Venue
Nucleic Acids Research
Publisher
Oxford University Press (OUP)
Published
2020-02-29
Volume
48
Issue
6
Pages
2866-2879
ISSN
  • 0305-1048 (ISSN-L)
  • 1362-4962
DOI
10.1093/nar/gkaa123
PMC
PMC7102942
OpenAlex
W3007581139
Cited by
25
References
14
Citations by year
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FWCI
1.05
Type
journal article
Language
en
Open access
Licence
Locations
  • Nucleic Acids Research (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Apollo (University of Cambridge) (submittedVersion, cc-by)
  • Apollo (cc-by)
Funders
  • Biotechnology and Biological Sciences Research Council
  • Wellcome Trust (WT107881)
  • Medical Research Council (MC_UU_00002/4, MC-A652-5QA20)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
Keywords
cis-regulatory modules, transcription factor binding, long-range gene regulation, natural genetic variation, allelic variation, transcriptional regulation, 3D genome organization, promoter capture Hi-C, distal enhancers, lymphoblastoid cell lines, linkage disequilibrium
MeSH terms
Base Sequence, Binding Sites, Chromatin, Gene Expression Regulation, Promoter Regions, Genetic, Protein Binding, Transcription Factors, Transcription, Genetic, Genes, Reporter, Quantitative Trait Loci

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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