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• W2786174959 abstract "Gene enhancer knockout phenotypes and analysis of enhancer activity patterns show that developmental genes are regulated by multiple redundant enhancers in mouse embryos. Enhancers are short sections of DNA that, when bound by specific proteins, regulate the level of transcription of a target gene. Len Pennacchio and colleagues examine the impact of enhancer redundancy on gene regulation in mouse limb development by deleting one or a combination of ten highly conserved enhancers located near seven genes that are required for limb development. While none of the ten individual enhancer deletions resulted in noticeable changes in limb morphology, the deletion of pairs of enhancers near the same genes resulted in altered limb development phenotypes. Analysing mouse ENCODE data, the authors find that enhancers near the same developmentally expressed gene commonly show similar activity patterns in the same tissue. They provide a statistical framework for estimating the number of enhancers that regulate each gene during development. 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 unclear1,2. 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." @default.
• W2786174959 created "2018-02-23" @default.
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• W2786174959 date "2018-01-31" @default.
• W2786174959 modified "2023-10-05" @default.
• W2786174959 title "Enhancer redundancy provides phenotypic robustness in mammalian development" @default.
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• W2786174959 doi "https://doi.org/10.1038/nature25461" @default.
• W2786174959 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/5808607" @default.
• W2786174959 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/29420474" @default.
• W2786174959 hasPublicationYear "2018" @default.
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