Affinity-optimizing enhancer variants disrupt development.
Affinity-optimizing enhancer variants disrupt development.
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DOI：
10.1038/s41586-023-06922-8
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发表时间：
2024-02
期刊：
影响因子：
64.8
通讯作者：
Farley, Emma K.
中科院分区：
文献类型：
--
作者：
Lim, Fabian;Solvason, Joe J.;Ryan, Genevieve E.;Le, Sophia H.;Jindal, Granton A.;Steffen, Paige;Jandu, Simran K.;Farley, Emma K.
增强子控制基因表达的位置和时间，并包含与疾病相关的大多数变异。ZRS可以说是研究最充分的脊椎动物增强剂，它介导Shh在发育中的肢体中的表达。ZRS中的31个人类单核苷酸变异(SNV)与多指症有关。然而，这种增强子如何编码组织特异性活动，以及SNV改变位数的机制还知之甚少。在这里，我们表明ZRs内的ETS位点是低亲和力的，并确定了一个亲和力极低的功能性ETS位点ETS-A。两个人类SNV和一个合成突变体微妙地优化了ETS-A的结合亲和力，相对于最强的ETS结合序列，从15%微妙地优化到25%左右，并导致具有相同外显率和严重程度的多指。亲和力的增加会导致表型更具渗透性和严肃性。ZRs中其他Ets位点的亲和力优化SNV，以及Ets中各种增强子中的干扰素调节因子、HOX和激活蛋白 1(AP-1)位点，都会导致功能获得基因表达。增强剂中亲和力不佳的结合位点的流行在基因组中造成了一个漏洞，从而优化亲和力的SNV，即使是轻微的，也可能是致病的。在基因组中寻找亲和力优化的SNV可以提供一种机械方法来识别导致增强型疾病的因果变异。低亲和力的转录因子结合位点普遍存在于整个基因组中，即使是轻微增加结合亲和力的单核苷酸变化也可能导致功能获得基因的表达和表型(如多指)。
Enhancers control the location and timing of gene expression and contain the majority of variants associated with disease. The ZRS is arguably the most well-studied vertebrate enhancer and mediates the expression of Shh in the developing limb. Thirty-one human single-nucleotide variants (SNVs) within the ZRS are associated with polydactyly. However, how this enhancer encodes tissue-specific activity, and the mechanisms by which SNVs alter the number of digits, are poorly understood. Here we show that the ETS sites within the ZRS are low affinity, and identify a functional ETS site, ETS-A, with extremely low affinity. Two human SNVs and a synthetic variant optimize the binding affinity of ETS-A subtly from 15% to around 25% relative to the strongest ETS binding sequence, and cause polydactyly with the same penetrance and severity. A greater increase in affinity results in phenotypes that are more penetrant and more severe. Affinity-optimizing SNVs in other ETS sites in the ZRS, as well as in ETS, interferon regulatory factor (IRF), HOX and activator protein 1 (AP-1) sites within a wide variety of enhancers, cause gain-of-function gene expression. The prevalence of binding sites with suboptimal affinity in enhancers creates a vulnerability in genomes whereby SNVs that optimize affinity, even slightly, can be pathogenic. Searching for affinity-optimizing SNVs in genomes could provide a mechanistic approach to identify causal variants that underlie enhanceropathies. Low-affinity transcription factor binding sites are prevalent across the genome, and single nucleotide changes that increase binding affinity even slightly can cause gain-of-function gene expression and phenotypes (such as polydactyly).
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DOI：
10.1126/science.1162327
发表时间：
2009-06-26
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Badis G;Berger MF;Philippakis AA;Talukder S;Gehrke AR;Jaeger SA;Chan ET;Metzler G;Vedenko A;Chen X;Kuznetsov H;Wang CF;Coburn D;Newburger DE;Morris Q;Hughes TR;Bulyk ML
通讯作者：
Bulyk ML
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
14.9
作者：
Banerjee AR;Kim YJ;Kim TH
通讯作者：
Kim TH
影响因子：
8.8
作者：
Lettice LA;Devenney P;De Angelis C;Hill RE
通讯作者：
Hill RE
影响因子：
5.3
作者：
Klar, M;Bode, J
通讯作者：
Bode, J