ArticleNature2018
Enhancer redundancy provides phenotypic robustness in mammalian development.
Article in Nature, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 406 papers.
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406 citing papers in PubMed, 701 citations in OpenAlex.
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- The future objectives of the International Mouse Phenotyping Consortium (IMPC): functional evaluation of human disease-relevant cis-regulatory elements in the mouse genome.Mammalian genome : official journal of the International Mammalian Genome Society · 2026Article
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- Analysis of 14q12 microdeletions reveals novel regulatory loci for the neurodevelopmental disorder-related gene FOXG1.Nature communications · 2026Article
- Genome architecture shapes the evolutionary origins of redundant enhancers in fly and mouse.bioRxiv : the preprint server for biology · 2026Article
- Advances and clinical potential of epigenome editing.Cellular and molecular life sciences : CMLS · 2026Review
- Cell differentiation can underpin the reproducibility of morphogenesis.PLoS computational biology · 2026Article
- Genome-Wide Annotation of Promoter-Enhancer Interactions via Chromatin Loops in the Hybrid Rat Diversity Panel.bioRxiv : the preprint server for biology · 2026Article
- Massively parallel reporter assay-informed modeling improves prediction of context-specific enhancer-gene regulatory interactions.Nucleic acids research · 2026Article
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- Genomic approaches for understanding the evolution of the human brain.Nature neuroscience · 2026Review
- Distinct mechanisms decommission redundant enhancers to facilitate phenotypic evolution.Science advances · 2026Article
- Enhancer hubs govern chromatin topology and Th17 cell identity.bioRxiv : the preprint server for biology · 2026Article
- Regulation of murine follicle-stimulating hormone β subunit transcription by newly identified enhancers.Endocrinology · 2026Article
346 more citing papers are in PubMed but not listed here.
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20 authors at 3 institutions in 2 countries.
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Abstract
Distant-acting tissue-specific enhancers, which regulate gene expression, vastly outnumber protein-coding genes in mammalian genomes, but the functional importance of this regulatory complexity remains unclear. Here we show that the pervasive presence of multiple enhancers with similar activities near the same gene confers phenotypic robustness to loss-of-function mutations in individual enhancers. We used genome editing to create 23 mouse deletion lines and inter-crosses, including both single and combinatorial enhancer deletions at seven distinct loci required for limb development. Unexpectedly, none of the ten deletions of individual enhancers caused noticeable changes in limb morphology. By contrast, the removal of pairs of limb enhancers near the same gene resulted in discernible phenotypes, indicating that enhancers function redundantly in establishing normal morphology. In a genetic background sensitized by reduced baseline expression of the target gene, even single enhancer deletions caused limb abnormalities, suggesting that functional redundancy is conferred by additive effects of enhancers on gene expression levels. A genome-wide analysis integrating epigenomic and transcriptomic data from 29 developmental mouse tissues revealed that mammalian genes are very commonly associated with multiple enhancers that have similar spatiotemporal activity. Systematic exploration of three representative developmental structures (limb, brain and heart) uncovered more than one thousand cases in which five or more enhancers with redundant activity patterns were found near the same gene. Together, our data indicate that enhancer redundancy is a remarkably widespread feature of mammalian genomes that provides an effective regulatory buffer to prevent deleterious phenotypic consequences upon the loss of individual enhancers.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.