ArticlePLoS genetics2014
Subtle changes in motif positioning cause tissue-specific effects on robustness of an enhancer's activity.
Article in PLoS genetics, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 36 papers.
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36 citing papers in PubMed, 72 citations in OpenAlex.
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- A map of cis-regulatory modules and constituent transcription factor binding sites in 80% of the mouse genome.BMC genomics · 2022Article
- Characterization of sequence determinants of enhancer function using natural genetic variation.eLife · 2022Article
- DeepSTARR predicts enhancer activity from DNA sequence and enables the de novo design of synthetic enhancers.Nature genetics · 2022Article
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- A combinatorial cis-regulatory logic restricts color-sensing Rhodopsins to specific photoreceptor subsets in Drosophila.PLoS genetics · 2021Article
- Base-resolution models of transcription-factor binding reveal soft motif syntax.Nature genetics · 2021Article
- A High-Throughput Genome-Integrated Assay Reveals Spatial Dependencies Governing Tcf7l2 Binding.Cell systems · 2020Article
- Functional genomic approaches to elucidate the role of enhancers during development.Wiley interdisciplinary reviews. Systems biology and medicine · 2020Review
- Assessing sufficiency and necessity of enhancer activities for gene expression and the mechanisms of transcription activation.Genes & development · 2018Review
- Synthetic enhancer design by in silico compensatory evolution reveals flexibility and constraint in cis-regulation.BMC systems biology · 2017Article
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Authors and funding
6 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Deciphering the specific contribution of individual motifs within cis-regulatory modules (CRMs) is crucial to understanding how gene expression is regulated and how this process is affected by sequence variation. But despite vast improvements in the ability to identify where transcription factors (TFs) bind throughout the genome, we are limited in our ability to relate information on motif occupancy to function from sequence alone. Here, we engineered 63 synthetic CRMs to systematically assess the relationship between variation in the content and spacing of motifs within CRMs to CRM activity during development using Drosophila transgenic embryos. In over half the cases, very simple elements containing only one or two types of TF binding motifs were capable of driving specific spatio-temporal patterns during development. Different motif organizations provide different degrees of robustness to enhancer activity, ranging from binary on-off responses to more subtle effects including embryo-to-embryo and within-embryo variation. By quantifying the effects of subtle changes in motif organization, we were able to model biophysical rules that explain CRM behavior and may contribute to the spatial positioning of CRM activity in vivo. For the same enhancer, the effects of small differences in motif positions varied in developmentally related tissues, suggesting that gene expression may be more susceptible to sequence variation in one tissue compared to another. This result has important implications for human eQTL studies in which many associated mutations are found in cis-regulatory regions, though the mechanism for how they affect tissue-specific gene expression is often not understood.
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