MYC基因座的CRISPR诱变揭示一个可成药的超保守RNA元件

MYC基因座的CRISPR诱变揭示一个可成药的超保守RNA元件

作者： 小柯机器人 发布时间：2026/11/15 19:58:37

本期文章：《细胞》：Online/在线发表

2026年，美国哥伦比亚大学欧文医学中心瓦格洛斯内科医学院心内科Wu Xuebing等科学家在《细胞》发表研究，利用CRISPR诱变绘制了MYC基因座的功能图谱，发现了一个可成药的超保守RNA元件。

非编码序列构成人类基因组的大部分，但其功能意义在很大程度上仍不清楚。研究人员利用近PAMless、高保真SpRY-Cas9进行CRISPR平铺诱变，以碱基对分辨率绘制了整个人类基因——10 kb MYC基因座——的适应度景观。这一无偏探究揭示，67%的功能必需碱基对是非编码的。必需非编码碱基对在人类群体中受到强约束，但在物种间显示出有限的演化保守性。在这一景观中，研究人员在3′非翻译区（UTR）鉴定出一个超保守非编码RNA元件，该元件通过与hnRNP L相互作用促进MYC mRNA的核周定位和MYC蛋白的核定位。靶向该元件的空间位阻反义寡核苷酸（ASOs）选择性消除多种MYC依赖性癌细胞，并抑制患者来源肿瘤类器官的生长。总之，这些发现确立了非编码序列作为功能遗传信息的主要载体，并鉴定出一个治疗上可操作的RNA元件，靶向该元件可破坏MYC驱动的癌症。

附：英文原文

Title: CRISPR mutagenesis of the MYC locus reveals a druggable ultraconserved RNA element

Author: Peiguo Shi, Feiyue Yang, Tala FNU, Wesley Huang, Linqing Xing, Shah Alam, Wangyang Dai, Alexis O. Aparicio, Colin H. Kalicki, Aditi Trehan, Michael R. Murphy, Esther R. Rotlevi, Prajish Iyer, Lili Wang, Sara Zaccara, Muredach P. Reilly, Ya Cheng Liao, Chaolin Zhang, Jianwen Que, Xuebing Wu

Issue&Volume:

Abstract: Noncoding sequences comprise most of the human genome; however, their functional significance remains largely elusive. Using CRISPR tiling mutagenesis with near-PAMless, high-fidelity SpRY-Cas9, we mapped the fitness landscape of an entire human gene, the 10-kb MYC locus, at base-pair resolution. This unbiased interrogation revealed that 67% of functionally essential base pairs are noncoding. Essential noncoding base pairs are under strong constraint in the human population but show limited evolutionary conservation across species. Within this landscape, we identified an ultraconserved noncoding RNA element in the 3′ untranslated region (UTR) that promotes perinuclear localization of MYC mRNA and nuclear localization of MYC protein through interaction with hnRNP L. Steric-blocking antisense oligonucleotides (ASOs) targeting this element selectively eliminate diverse MYC-dependent cancer cells and inhibit growth of patient-derived tumor organoids. Together, these findings establish noncoding sequences as major carriers of functional genetic information and identify a therapeutically actionable RNA element whose targeting disrupts MYC-driven cancer.

DOI: 10.1016/j.cell.2026.10.002

Source: https://www.cell.com/cell/abstract/S0092-8674(26)01213-4

主题：MYC基因座