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Cited by 96Genomics and Chromatin DynamicsGenetic Associations and EpidemiologyChromosomal and Genetic Variations

Spurious transcription factor binding: Non‐functional or genetically redundant?

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Spivakov, Mikhail·2014·BioEssays
DOI 10.1002/bies.201400036PMC PMC4230394
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Abstract

Transcription factor binding sites (TFBSs) on the DNA are generally accepted as the key nodes of gene control. However, the multitudes of TFBSs identified in genome‐wide studies, some of them seemingly unconstrained in evolution, have prompted the view that in many cases TF binding may serve no biological function. Yet, insights from transcriptional biochemistry, population genetics and functional genomics suggest that rather than segregating into ‘functional’ or ‘non‐functional’, TFBS inputs to their target genes may be generally cumulative, with varying degrees of potency and redundancy. As TFBS redundancy can be diminished by mutations and environmental stress, some of the apparently ‘spurious’ sites may turn out to be important for maintaining adequate transcriptional regulation under these conditions. This has significant implications for interpreting the phenotypic effects of TFBS mutations, particularly in the context of genome‐wide association studies for complex traits.

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  • Enhancer conservation is typically modular, commonly preserving the sets of binding sites for the required transcription factors, but often not their exact sequence and orientation.

    “Instead, enhancer conservation is typically “modular”, commonly preserving the sets of binding sites for the required TFs, but often not their exact sequence and orientation [101–109].”

    From Transcriptional enhancers and their communication with gene promoters (2021) · cites this paper as [107]

    In ‘Dose of activation’ as an evolutionary trait (page unavailable), the paper says regulatory regions can retain function despite low base-by-base conservation and turnover of transcription-factor binding sites. In ‘Do “doses” add up at multi-TF enhancers?’ (page unavailable), it describes flexible enhancer organisation, but it does not establish that conserved enhancers commonly preserve the same sets of required transcription factors or address binding-site orientation. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • When an enhancer comes into proximity with a compatible promoter, it transmits a dose of activation that results in a certain level of transcriptional output.

    “when an enhancer comes into proximity with a compatible promoter, it transmits to it a “dose of activation” that results in a certain level of transcriptional output [107].”

    From Transcriptional enhancers and their communication with gene promoters (2021) · cites this paper as [107]

    In “The output of TF binding as a ‘dose of activation’” (page unavailable), the paper proposes that TF binding sites can contribute activating doses to promoters through DNA looping and that promoters respond to the total dose received. The citing sentence captures that model but states it categorically for an enhancer, whereas the paper presents it as a possibility and describes transcriptional output as a response to inputs from multiple binding sites. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

  • Some enhancer variants that appear functionally neutral when tested under normal steady-state conditions may show cryptic effects under stress or upon stimulus response.

    “Notably, some enhancer variants that appear functionally neutral when tested under normal steady-state conditions may show “cryptic” effects under stress or upon stimulus response [107, 226, 227].”

    From Transcriptional enhancers and their communication with gene promoters (2021) · cites this paper as [107]

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Authors
Spivakov, M.
Affiliations
Babraham Institute (GB)
Corresponding author
Spivakov, Mikhail
ORCID
Spivakov, Mikhail
Venue
BioEssays
Publisher
Wiley
Published
2014-05-30
Volume
36
Issue
8
Pages
798-806
ISSN
  • 0265-9247 (ISSN-L)
  • 1521-1878
DOI
10.1002/bies.201400036
PMC
PMC4230394
OpenAlex
W1557274850
Cited by
96
References
16
Citations by year
2026: 4 · 2025: 10 · 2024: 12 · 2023: 7 · 2022: 5 · 2021: 16 · 2020: 7 · 2019: 2 · 2018: 9 · 2017: 6 · 2016: 9 · 2015: 8 · 2014: 1
FWCI
0.75
Type
journal article
Language
en
Open access
Licence
Locations
  • BioEssays (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
Biotechnology and Biological Sciences Research Council
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 › Agricultural and Biological Sciences › Plant Science › Chromosomal and Genetic Variations
Keywords
transcription factor binding sites, transcriptional regulation, gene redundancy, genome-wide association study, complex traits, environmental stress
MeSH terms
Animals, Binding Sites, Humans, Promoter Regions, Genetic, Protein Binding, Transcription Factors, Transcription, Genetic, Transcriptional Activation, Evolution, Molecular

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