Enhancer redundancy provides phenotypic robustness in mammalian development.
Enhancer redundancy provides phenotypic robustness in mammalian development.
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DOI：
10.1038/nature25461
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发表时间：
2018-02-08
期刊：
影响因子：
64.8
通讯作者：
Pennacchio LA
中科院分区：
文献类型：
--
作者：
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
在哺乳动物基因组中，远作用组织特异性增强子的数量远远超过蛋白质编码基因，但这种调控复杂性的功能意义仍然没有得到充分的了解。在这里，我们表明，在同一基因附近具有相似活性的多个增强子的普遍存在赋予了单个增强子对功能丧失突变的表型稳健性。我们使用基因组编辑技术创建了23个小鼠缺失系和交叉，包括肢体发育所需的7个不同位点的单个和组合增强子缺失。令人惊讶的是，10个单个增强子的缺失都没有引起肢体形态的明显变化。相反，去除同一基因附近的肢体增强子对会导致可识别的表型，这表明增强子在建立正常形态方面具有冗余功能。在靶基因基线表达降低致敏的遗传背景中，即使单个增强子缺失也会导致肢体异常，这表明功能冗余是由增强子对基因表达水平的加性作用赋予的。一项整合29个发育小鼠组织的表观基因组和转录组数据的全基因组分析显示，哺乳动物基因通常与具有相似时空活性的多个增强子相关。对三个具有代表性的发育结构（肢体、大脑、心脏）的系统探索发现，在一千多个案例中，在同一基因附近发现了五个或更多具有冗余活动模式的增强子。综上所述，我们的数据表明，增强子冗余是哺乳动物基因组中一个非常普遍的特征，并提供了一个有效的调节缓冲，防止在单个增强子丢失时产生有害的表型后果。
Distant-acting tissue-specific enhancers vastly outnumber protein-coding genes in mammalian genomes, but the functional significance of this regulatory complexity remains insufficiently understood. 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.
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DOI：
10.1093/bioinformatics/btu638
发表时间：
2015-01-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Anders S;Pyl PT;Huber W
通讯作者：
Huber W
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
7
作者：
Harrow J;Frankish A;Gonzalez JM;Tapanari E;Diekhans M;Kokocinski F;Aken BL;Barrell D;Zadissa A;Searle S;Barnes I;Bignell A;Boychenko V;Hunt T;Kay M;Mukherjee G;Rajan J;Despacio-Reyes G;Saunders G;Steward C;Harte R;Lin M;Howald C;Tanzer A;Derrien T;Chrast J;Walters N;Balasubramanian S;Pei B;Tress M;Rodriguez JM;Ezkurdia I;van Baren J;Brent M;Haussler D;Kellis M;Valencia A;Reymond A;Gerstein M;Guigó R;Hubbard TJ
通讯作者：
Hubbard TJ
影响因子：
4
作者：
Barolo, Scott
通讯作者：
Barolo, Scott
影响因子：
10.5
作者：
Akiyama, H;Chaboissier, MC;de Crombrugghe, B
通讯作者：
de Crombrugghe, B