Gene Regulatory Enhancers with Evolutionarily Conserved Activity Are More Pleiotropic than Those with Species-Specific Activity.
Gene Regulatory Enhancers with Evolutionarily Conserved Activity Are More Pleiotropic than Those with Species-Specific Activity.
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DOI：
10.1093/gbe/evx194
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发表时间：
2017-10-01
影响因子：
3.3
通讯作者：
Capra JA
中科院分区：
文献类型：
--
作者：
Fish A;Chen L;Capra JA
调节活性和基因表达的研究揭示了一个有趣的二分法：物种之间的正向序列的调节活性有很大的周转，然而，正向基因的表达水平在很大程度上是保守的。了解远端调控元件（例如增强子）如何进化和发挥功能至关重要，因为基因表达水平的改变可以驱动物种之间复杂疾病和功能差异的发展。在这项研究中，我们调查了哺乳动物进化过程中正向序列的调节增强子活性保守性的决定因素。使用从10种不同哺乳动物的全基因组蛋白修饰谱中鉴定的肝脏增强子，我们比较了在所有物种中表现出调节活性的正向序列（保守活性增强子）与仅在单个物种中具有活性的共享序列（物种特异性活性增强子）。保守活性增强子比物种特异性活性增强子具有更大的调节潜力，如通过转录因子结合基序的密度和多样性来量化的。与其更大的调节潜力相一致，保守活性增强子在人类中比物种特异性活性增强子具有更大的调节活性：它们在更多的细胞环境中具有活性，并且它们比物种特异性活性增强子调节更多的基因。此外，由保守活性增强子调控的基因在更多的组织中表达，并且比由物种特异性活性增强子靶向的基因对功能丧失突变的耐受性更低。这些在基因调控的各个阶段的一致结果表明，保守活性增强子比它们的物种特异性活性对应物更具多效性。这表明多效性与哺乳动物进化过程中的调节保守性有关。
Studies of regulatory activity and gene expression have revealed an intriguing dichotomy: There is substantial turnover in the regulatory activity of orthologous sequences between species; however, the expression level of orthologous genes is largely conserved. Understanding how distal regulatory elements, for example, enhancers, evolve and function is critical, as alterations in gene expression levels can drive the development of both complex disease and functional divergence between species. In this study, we investigated determinants of the conservation of regulatory enhancer activity for orthologous sequences across mammalian evolution. Using liver enhancers identified from genome-wide histone modification profiles in ten diverse mammalian species, we compared orthologous sequences that exhibited regulatory activity in all species (conserved-activity enhancers) to shared sequences active only in a single species (species-specific-activity enhancers). Conserved-activity enhancers have greater regulatory potential than species-specific-activity enhancers, as quantified by both the density and diversity of transcription factor binding motifs. Consistent with their greater regulatory potential, conserved-activity enhancers have greater regulatory activity in humans than species-specific-activity enhancers: They are active across more cellular contexts, and they regulate more genes than species-specific-activity enhancers. Furthermore, the genes regulated by conserved-activity enhancers are expressed in more tissues and are less tolerant of loss-of-function mutations than those targeted by species-specific-activity enhancers. These consistent results across various stages of gene regulation demonstrate that conserved-activity enhancers are more pleiotropic than their species-specific-activity counterparts. This suggests that pleiotropy is associated with the conservation of regulatory across mammalian evolution.
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DOI：
10.1093/bioinformatics/btr064
发表时间：
2011-04-01
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Grant CE;Bailey TL;Noble WS
通讯作者：
Noble WS
DOI：
10.1038/nrg3229
发表时间：
2012-06-18
期刊：
Nature reviews. Genetics
影响因子：
--
作者：
通讯作者：
--
影响因子：
3.7
作者：
Kapur K;Schüpbach T;Xenarios I;Kutalik Z;Bergmann S
通讯作者：
Bergmann S
影响因子：
10.7
作者：
Amoutzias, G. D.;Veron, A. S.;Robertson, D. L.
通讯作者：
Robertson, D. L.
DOI：
10.1126/science.1262110
发表时间：
2015-05-08
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
GTEx Consortium
通讯作者：
GTEx Consortium