长期进化限制揭示了人类X染色体上的顺式调控相互作用。
Long-range evolutionary constraints reveal cis-regulatory interactions on the human X chromosome.
作者信息
Naville Magali, Ishibashi Minaka, Ferg Marco, Bengani Hemant, Rinkwitz Silke, Krecsmarik Monika, Hawkins Thomas A, Wilson Stephen W, Manning Elizabeth, Chilamakuri Chandra S R, Wilson David I, Louis Alexandra, Lucy Raymond F, Rastegar Sepand, Strähle Uwe, Lenhard Boris, Bally-Cuif Laure, van Heyningen Veronica, FitzPatrick David R, Becker Thomas S, Roest Crollius Hugues
机构信息
1] Ecole Normale Supérieure, Institut de Biologie de l'ENS, IBENS, 46 rue d'Ulm, Paris F-75005, France [2] CNRS, UMR 8197, Paris F-75005, France [3] Inserm, U1024, Paris F-75005, France.
Brain and Mind Research Institute, Sydney Medical School, University of Sydney, Camperdown, New South Wales 2050, Australia.
出版信息
Nat Commun. 2015 Apr 24;6:6904. doi: 10.1038/ncomms7904.
Enhancers can regulate the transcription of genes over long genomic distances. This is thought to lead to selection against genomic rearrangements within such regions that may disrupt this functional linkage. Here we test this concept experimentally using the human X chromosome. We describe a scoring method to identify evolutionary maintenance of linkage between conserved noncoding elements and neighbouring genes. Chromatin marks associated with enhancer function are strongly correlated with this linkage score. We test >1,000 putative enhancers by transgenesis assays in zebrafish to ascertain the identity of the target gene. The majority of active enhancers drive a transgenic expression in a pattern consistent with the known expression of a linked gene. These results show that evolutionary maintenance of linkage is a reliable predictor of an enhancer's function, and provide new information to discover the genetic basis of diseases caused by the mis-regulation of gene expression.
增强子能够在很长的基因组距离上调控基因转录。人们认为这会导致针对此类区域内可能破坏这种功能联系的基因组重排的选择。在此，我们使用人类X染色体通过实验来验证这一概念。我们描述了一种评分方法，以确定保守非编码元件与相邻基因之间连锁的进化维持情况。与增强子功能相关的染色质标记与该连锁评分密切相关。我们通过斑马鱼转基因实验对1000多个假定的增强子进行测试，以确定靶基因的身份。大多数活性增强子驱动转基因表达的模式与连锁基因的已知表达一致。这些结果表明，连锁的进化维持是增强子功能的可靠预测指标，并为发现因基因表达调控异常引起的疾病的遗传基础提供了新信息。
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