清华大学张强锋等研究人员合作发现，计算预测和实验验证确定从斑马鱼到人类的功能保守的lncRNA。2024年1月9日，国际知名学术期刊《自然—遗传学》在线发表了这一成果。

研究人员介绍了长非编码 RNA（lncRNA）Homology Explorer (lncHOME)，它是一种计算管线，能识别一类独特的长非编码RNA（lncRNA），这些RNA具有保守的基因组位置和RNA结合蛋白（RBP）结合位点模式（coPARSE-lncRNA）。值得注意的是，几百个人类coPARSE-lncRNA在演化过程中可以追溯到斑马鱼。

利用CRISPR-Cas12a基因敲除和拯救实验，研究人员发现敲除许多人类coPARSE-lncRNA会导致细胞增殖缺陷，而这些缺陷随后会被预测的斑马鱼同源物所拯救。敲除斑马鱼胚胎中的coPARSE-lncRNA会导致严重的发育迟缓，而人类同源物则能挽救这种迟缓。此外，研究人员还验证了人类、小鼠和斑马鱼coPARSE-lncRNA同源物倾向于结合相似的RBP，其保守功能依赖于特定的RBP结合位点。

总之，这项研究展示了一种研究lncRNA功能保守性的综合方法，并揭示了许多lncRNA在调控脊椎动物生理方面的作用。

研究人员表示，对lncRNA的功能研究因缺乏评估其进化的方法而受到阻碍。

附：英文原文

Title: Computational prediction and experimental validation identify functionally conserved lncRNAs from zebrafish to human

Author: Huang, Wenze, Xiong, Tuanlin, Zhao, Yuting, Heng, Jian, Han, Ge, Wang, Pengfei, Zhao, Zhihua, Shi, Ming, Li, Juan, Wang, Jiazhen, Wu, Yixia, Liu, Feng, Xi, Jianzhong Jeff, Wang, Yangming, Zhang, Qiangfeng Cliff

Issue&Volume: 2024-01-09

Abstract: Functional studies of long noncoding RNAs (lncRNAs) have been hindered by the lack of methods to assess their evolution. Here we present lncRNA Homology Explorer (lncHOME), a computational pipeline that identifies a unique class of long noncoding RNAs (lncRNAs) with conserved genomic locations and patterns of RNA-binding protein (RBP) binding sites (coPARSE-lncRNAs). Remarkably, several hundred human coPARSE-lncRNAs can be evolutionarily traced to zebrafish. Using CRISPR–Cas12a knockout and rescue assays, we found that knocking out many human coPARSE-lncRNAs led to cell proliferation defects, which were subsequently rescued by predicted zebrafish homologs. Knocking down coPARSE-lncRNAs in zebrafish embryos caused severe developmental delays that were rescued by human homologs. Furthermore, we verified that human, mouse and zebrafish coPARSE-lncRNA homologs tend to bind similar RBPs with their conserved functions relying on specific RBP-binding sites. Overall, our study demonstrates a comprehensive approach for studying the functional conservation of lncRNAs and implicates numerous lncRNAs in regulating vertebrate physiology.

DOI: 10.1038/s41588-023-01620-7

Source: https://www.nature.com/articles/s41588-023-01620-7