Characterization of sequence determinants of enhancer function using natural genetic variation
- Harvard University, United States
- Rockefeller University, Howard Hughes Medical Institute, United States
- Memorial Sloan Kettering Cancer Center, United States
Abstract
Sequence variation in enhancers that control cell type-specific gene transcription contributes significantly to phenotypic variation within human populations. However, it remains difficult to predict precisely the effect of any given sequence variant on enhancer function due to the complexity of DNA sequence motifs that determine transcription factor (TF) binding to enhancers in their native genomic context. Using F1-hybrid cells derived from crosses between distantly related inbred strains of mice, we identified thousands of enhancers with allele-specific TF binding and/or activity. We find that genetic variants located within the central region of enhancers are most likely to alter TF binding and enhancer activity. We observe that the AP-1 family of TFs (Fos/Jun) are frequently required for binding of TEAD TFs and for enhancer function. However, many sequence variants outside of core motifs for AP-1 and TEAD also impact enhancer function, including sequences flanking core TF motifs and AP-1 half sites. Taken together, these data represent one of the most comprehensive assessments of allele-specific TF binding and enhancer function to date and reveal how sequence changes at enhancers alter their function across evolutionary timescales.
Data availability
We submitted our data to GEO, and it is now accessible via GSE193728.
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Characterization of sequence determinants of enhancer function using natural genetic variationNCBI Gene Expression Omnibus, GSE193728.
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Index and biological spectrum of accessible DNA elements in the human genomehttps://doi.org/10.1101/822510.
Article and author information
Author details
Funding
NIH Office of the Director (T32EY00711030)
- Marty G Yang
NIH Office of the Director (T32AG000222)
- Marty G Yang
National Science Foundation (DGE0946799)
- Emi Ling
National Science Foundation (DGE1144152)
- Emi Ling
NIH Office of the Director (R01 NS115965)
- Michael E Greenberg
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Stephen CJ Parker, University of Michigan, United States
Ethics
Animal experimentation: All animal experiments were approved by the National Institutes of Health and the Harvard Medical School Institutional Animal Care and Use Committee and were conducted in compliance with the relevant ethical regulations (Protocol # IS00000074-3)
Version history
- Preprint posted: December 18, 2021 (view preprint)
- Received: December 18, 2021
- Accepted: August 30, 2022
- Accepted Manuscript published: August 31, 2022 (version 1)
- Version of Record published: November 14, 2022 (version 2)
Copyright
© 2022, Yang et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Characterization of sequence determinants of enhancer function using natural genetic variation
eLife 11:e76500.
https://doi.org/10.7554/eLife.76500
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