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PreprintCited by 162Genomics and Chromatin DynamicsGene Regulatory Network AnalysisProtein Structure and Dynamics

How subtle changes in 3D structure can create large changes in transcription

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Xiao, Jordan, Hafner, Antonina, Boettiger, Alistair N.·2020·eLife
DOI 10.1101/2020.10.22.351395PMC PMC8352591

Preprint — published as 10.7554/elife.64320 · Paper page

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Abstract

Animal genomes are organized into topologically associated domains (TADs), which exhibit more intra-domain than inter-domain contact. However, the absolute difference in contact is usually no more than twofold, even though disruptions to TAD boundaries can change gene expression by 8-10 fold. Existing models fail to explain this superlinear transcriptional response to changes in genomic contact. Here, we propose a futile cycle model where an enzyme stimulated by association with its products can exhibit bistability and hysteresis, allowing a small increase in enhancer-promoter contact to produce a large change in expression without obvious correlation between E-P contact and promoter activity. Through mathematical analysis and stochastic simulation, we show that this system can create an illusion of enhancer-promoter specificity and explain the importance of weak TAD boundaries. It also offers a mechanism to reconcile recent global cohesin loop disruption and TAD boundary deletion experiments. We discuss the model in the context of these recent controversial experiments. Together, these analyses advance our interpretation and understanding of cis-regulatory contacts in controlling gene expression, and suggest new experimental directions.

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  • Biophysical modelling suggests that the same enhancer may have vastly unequal effects on different promoters depending on their intrinsic sensitivity to enhancer-promoter contacts, irrespective of the properties of a given enhancer.

    “biophysical modelling suggests that the same enhancer may have vastly unequal effects on different promoters depending on their intrinsic sensitivity to enhancer–promoter contacts (irrespectively of the properties of a given enhancer) [406].”

    From Transcriptional enhancers and their communication with gene promoters (2021) · cites this paper as [406]

  • An enhancer's contact with a promoter may facilitate the transition of the promoter from a low-activity state to a highly active state, which in turn may generate bursts at a higher frequency.

    “they propose that an enhancer’s contact with a promoter may facilitate the transition of the promoter from a low-activity state to a highly active state [405, 406], which in turn may generate bursts at a higher frequency.”

    From Transcriptional enhancers and their communication with gene promoters (2021) · cites this paper as [406]

  • Promoters may have a memory (hysteresis) of enhancer action.

    “This way, promoters may have a “memory” (hysteresis) of enhancer action [405, 406], reviving some early debates on this topic [527].”

    From Transcriptional enhancers and their communication with gene promoters (2021) · cites this paper as [406]

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Authors
Xiao, J., Hafner, A., & Boettiger, A. N.
Affiliations
Stanford University (US)
Corresponding author
Boettiger, Alistair N.
ORCID
Venue
eLife
Publisher
openRxiv
Published
2020-10-23
Volume
10
ISSN
2050-084X (ISSN-L)
DOI
10.1101/2020.10.22.351395
PMC
PMC8352591
OpenAlex
W3181995425
Cited by
162
References
0
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journal article
Language
en
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Licence
Locations
  • eLife (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Burroughs Wellcome Fund
  • Stanford University (GM008294)
  • National Institutes of Health (1dp2gm132935-01)
  • National Institute of General Medical Sciences (T32GM008294, DP2 GM132935)
  • National Institute of Diabetes and Digestive and Kidney Diseases (U01DK127419)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gene Regulatory Network Analysis
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
Keywords
topologically associating domains, TAD boundaries, enhancer-promoter interactions, gene expression regulation, bistability, hysteresis, 3D genome organization, stochastic gene expression, promoter activity
MeSH terms
Animals, Chromatin, Gene Expression Regulation, Humans, Hypersensitivity, Promoter Regions, Genetic, Transcription, Genetic, Genome, Computational Biology, Mice

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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