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10.1038/nature25461 http://scihub22266oqcxt.onion/10.1038/nature25461 C5808607!5808607!29420474     free     free     free Deprecated: Implicit conversion from float 227.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 227.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 227.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 227.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534       Nature 2018 ; 554 (7691): 239-43 Nephropedia Template TP {{tp|p=29420474|t=2018. Enhancer Redundancy Allows for Phenotypic Robustness in Mammalian Development |pdf=|usr=}}{{29420474}} gab.com Text Enhancer Redundancy Allows for Phenotypic Robustness in Mammalian Development JO: Nature http://www.kidney.de/pget.php?&tw=1&pmid=29420474 #FOAvip Distant-acting tissue-specific enhancers vastly outnumber protein-coding genes in mammalian genomes, but the functional significance of this regulatory complexity remains insufficiently understood1,2. 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 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, heart) uncovered more than a thousand cases in which five or more enhancers with redundant activity patterns were found near the same gene. Taken together, our data indicate that enhancer redundancy is a remarkably widespread feature of mammalian genomes and provides an effective regulatory buffer preventing deleterious phenotypic consequences upon loss of individual enhancers. Twit Text FOAVip Enhancer Redundancy Allows for Phenotypic Robustness in Mammalian Development ????Nature http://www.kidney.de/pget.php?&tw=1&pmid=29420474 #FOAvip Twit Text # Free Paper on # # # # # LINK http://www.kidney.de/pget.php?&tw=1&pmid=29420474 #FOAvip English Wikipedia <ref>{{Cite pmid|29420474}}</ref> Enhancer Redundancy Allows for Phenotypic Robustness in Mammalian Development #MMPMID29420474 Osterwalder M; Barozzi I; Tissières V; Fukuda-Yuzawa Y; Mannion BJ; Afzal SY; Lee EA; Zhu Y; Plajzer-Frick I; Pickle CS; Kato M; Garvin TH; Pham QT; Harrington AN; Akiyama JA; Afzal V; Lopez-Rios J; Dickel DE; Visel A; Pennacchio LA Nature 2018[Feb]; 554 (7691): 239-43 PMID29420474show ga Distant-acting tissue-specific enhancers vastly outnumber protein-coding genes in mammalian genomes, but the functional significance of this regulatory complexity remains insufficiently understood1,2. 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 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, heart) uncovered more than a thousand cases in which five or more enhancers with redundant activity patterns were found near the same gene. Taken together, our data indicate that enhancer redundancy is a remarkably widespread feature of mammalian genomes and provides an effective regulatory buffer preventing deleterious phenotypic consequences upon loss of individual enhancers. äEnhancer Redundancy Allows for Phenotypic Robustness in Mammalian Deve(epmc).pdf DeepDyve Pubget Overpricing