Faculty Opinions recommendation of Enhancer redundancy provides phenotypic robustness in mammalian development.
Year: 2018
Type: peer-review
Abstract: Distant-acting tissue-specific enhancers vastly outnumber protein-coding genes in mammalian genomes, but the functional significance of this regulatory complexity remains insufficiently understood 1,2 .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.Surprisingly, none of ten deletions of individual enhancers caused noticeable changes in limb morphology.In contrast, 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 genomewide analysis integrating epigenomic and transcriptomic data from 29 developmental mouse Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/
Author: Jane Skok
Institution: NYU Langone Health
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
Funders: National Science Foundation, U.S. Department of Energy, Novartis Foundation, Universität Basel, Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung, National Institutes of Health, National Heart, Lung, and Blood Institute, National Human Genome Research Institute, Lawrence Berkeley National Laboratory
Awards: G1026919566, G1079818582, G1143651532, G1286236842, Center for Mammalian Regulatory Genomics, G1863003419, G2343817717, G3083819904, Genome-Wide Resources for Transcriptional Enhancers Active in the Human Heart, G382641700, G42916606, Regulation of Cardiac Development in Health and Disease, G465867758, G4982041051, G7021921917, G7354628648, Functionally Assessing Transcriptional Enhancers In Vivo, G969889393
OpenAlex ID: W4232597326