近日，美国加州大学圣迭戈分校Emma K. Farley及其课题组发现，亲和优化增强子变体干扰发育。该研究于2024年1月17日在线发表于国际一流学术期刊《自然》。
研究人员表示，增强子控制着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可以说是脊椎动物中研究最深入的增强子，它介导着Shh在肢体发育过程中的表达。ZRS中的31个人类单核苷酸变异（SNV）与多指畸形有关。然而，人们对这一增强子如何编码组织特异性活性以及SNV改变手指数目的机制知之甚少。
研究人员发现ZRS内的ETS位点亲和力很低，并鉴定出一个亲和力极低的功能性ETS位点ETS-A。相对于最强的ETS结合序列，两个人类SNV和一个合成变体将ETS-A的结合亲和力从15%微妙地优化到25%左右，并导致具有相同渗透性和严重程度的多指畸形。亲和力的进一步提高会导致更高的通透性和更严重的表型。ZRS中其他ETS位点以及各种增强子中的ETS、干扰素调节因子（IRF）、HOX和激活蛋白1（AP-1）位点中的亲和力优化SNV，会导致功能增益基因表达。
增强子中普遍存在亲和力不理想的结合位点，这在基因组中造成了一个漏洞，即亲和力哪怕稍有优化的SNV也可能致病。在基因组中寻找亲和力最优化的SNV可提供一种机理方法，从而确定导致增强子病的因果变异。
附：英文原文
Title: Affinity-optimizing enhancer variants disrupt development
Author: Lim, Fabian, Solvason, Joe J., Ryan, Genevieve E., Le, Sophia H., Jindal, Granton A., Steffen, Paige, Jandu, Simran K., Farley, Emma K.
Issue&Volume: 2024-01-17
Abstract: Enhancers control the location and timing of gene expression and contain the majority of variants associated with disease1–3. The ZRS is arguably the most well-studied vertebrate enhancer and mediates the expression of Shh in the developing limb4. Thirty-one human single-nucleotide variants (SNVs) within the ZRS are associated with polydactyly4–6. 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).
DOI: 10.1038/s41586-023-06922-8
Source: https://www.nature.com/articles/s41586-023-06922-8
Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
官方网址：http://www.nature.com/
投稿链接：http://www.nature.com/authors/submit_manuscript.html
本期文章：《自然》：Online/在线发表
