A gain-of-function single nucleotide variant creates a new promoter which acts as an orientation-dependent enhancer-blocker.
A gain-of-function single nucleotide variant creates a new promoter which acts as an orientation-dependent enhancer-blocker.
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DOI：
10.1038/s41467-021-23980-6
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发表时间：
2021-06-21
影响因子：
16.6
通讯作者：
Higgs DR
中科院分区：
文献类型：
--
作者：
Bozhilov YK;Downes DJ;Telenius J;Marieke Oudelaar A;Olivier EN;Mountford JC;Hughes JR;Gibbons RJ;Higgs DR
许多与人类特征和遗传疾病相关的单核苷酸变异(SNV)被认为改变了现有调控元件的活性。一些SNV还可能产生全新的调节元件来改变基因表达，但它们这样做的机制在很大程度上是未知的。在这里，我们表明，在人类α-珠蛋白簇的一个不显著的区域中，单个碱基的变化就会产生一个全新的启动子和相关的单向转录本。这种SNV下调α-珠蛋白的表达，导致α-地中海贫血症。值得注意的是，位于α-珠蛋白基因和它们相关的超级增强子之间的新启动子以一种依赖于方向的方式破坏了它们的相互作用。综上所述，这些观察显示了基因组基本元件的顺序和方向如何决定基因表达模式，并支持活性基因可能像果蝇一样破坏哺乳动物中增强子-启动子相互作用的概念。最后，这些发现应该促使其他人充分评估位于已知调控元件之外的SNV是否通过创建新的调控元件而导致基因表达的变化。启动子作为潜在的绝缘元件在哺乳动物中的作用在很大程度上还没有被探索过。在这里，作者证明了α-珠蛋白基因中的一个单核苷酸变异形成了一个新的启动子，并作为一个方向依赖的增强子阻断绝缘体元件。
Many single nucleotide variants (SNVs) associated with human traits and genetic diseases are thought to alter the activity of existing regulatory elements. Some SNVs may also create entirely new regulatory elements which change gene expression, but the mechanism by which they do so is largely unknown. Here we show that a single base change in an otherwise unremarkable region of the human α-globin cluster creates an entirely new promoter and an associated unidirectional transcript. This SNV downregulates α-globin expression causing α-thalassaemia. Of note, the new promoter lying between the α-globin genes and their associated super-enhancer disrupts their interaction in an orientation-dependent manner. Together these observations show how both the order and orientation of the fundamental elements of the genome determine patterns of gene expression and support the concept that active genes may act to disrupt enhancer-promoter interactions in mammals as in Drosophila. Finally, these findings should prompt others to fully evaluate SNVs lying outside of known regulatory elements as causing changes in gene expression by creating new regulatory elements. The role of promoters as potential insulator elements has been largely unexplored in mammals. Here the authors show that a single nucleotide variant in the α-globin locus forms a new promoter and acts as an orientation-dependent enhancer-blocking insulator element.
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影响因子：
64.5
作者：
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通讯作者：
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影响因子：
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影响因子：
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通讯作者：
Blobel GA
影响因子：
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作者：
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