Deletion of Pax1 scoliosis-associated regulatory elements leads to a female-biased tail abnormality.
Deletion of Pax1 scoliosis-associated regulatory elements leads to a female-biased tail abnormality.
复制标题
Pax1 脊柱侧凸相关调节元件的缺失会导致女性偏向的尾部异常。
DOI：
10.1101/2023.04.12.536497
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
Ahituv,Nadav
中科院分区：
文献类型：
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作者：
Ushiki,Aki;Sheng,RoryR;Zhang,Yichi;Zhao,Jingjing;Nobuhara,Mai;Murray,Elizabeth;Ruan,Xin;Rios,JonathanJ;Wise,CarolA;Ahituv,Nadav
青少年特发性脊柱侧凸（AIS）是一种脊柱侧弯，具有性别二态性，女性发病率较高。一项全基因组关联研究在PAX1基因附近发现了一个女性特异性AIS易感基因座。在这里，我们使用小鼠增强子测定，三个小鼠增强子敲除，和随后的表型分析，以表征这一地区。使用小鼠增强子测定，我们表征了一个序列，PEC7，它重叠AIS相关的变体，并发现它是活跃的尾尖和椎间盘。去除PEC7或Xe1（附近的一种已知的硬化体增强子）或缺失这两种序列仅在Xe1和组合（Xe1+PEC7）敲除中导致扭结尾表型，仅后者显示雌性性别二态表型。这些小鼠品系的广泛表型表征暗示了性别二态性偏倚中的几个差异表达基因和雌激素信号传导。总之，我们的工作在功能上表征了AIS相关基因座，并剖析了其性二态性的机制。
Adolescent idiopathic scoliosis (AIS), a sideways curvature of the spine, is sexually dimorphic, with increased incidence in females. A genome-wide association study identified a female-specific AIS susceptibility locus near thePAX1gene. Here, we use mouse enhancer assays, three mouse enhancer knockouts, and subsequent phenotypic analyses to characterize this region. Using mouse enhancer assays, we characterize a sequence, PEC7, which overlaps the AIS-associated variant, and find it to be active in the tail tip and intervertebral disc. Removal of PEC7 or Xe1, a known sclerotome enhancer nearby, or deletion of both sequences lead to a kinky tail phenotype only in the Xe1 and combined (Xe1+PEC7) knockouts, with only the latter showing a female sex dimorphic phenotype. Extensive phenotypic characterization of these mouse lines implicates several differentially expressed genes and estrogen signaling in the sex dimorphic bias. In summary, our work functionally characterizes an AIS-associated locus and dissects the mechanism for its sexual dimorphism.