中国科学院生物物理研究所薛愿超团队发现，互补Alu序列介导增强子-启动子选择性。该项研究成果于2023年7月12日在线发表在《自然》杂志上。

研究人员表示，增强子通过与长程启动子结合来决定时空基因表达程序。然而，增强子如何找到它们的同源启动子仍然是未知的。研究人员最近开发了一种RNA原位构象测序技术，利用成对相互作用的增强子RNA和启动子衍生的非编码RNA来鉴定增强子-启动子的连接性。

研究人员应用该技术在另外6个细胞系中生成了高置信度的增强子-启动子RNA相互作用图谱。利用这些图谱，研究人员发现37.9%的增强子-启动子RNA相互作用位点与Alu序列重叠。这些成对相互作用的Alu和非Alu RNA序列倾向于互补并可能形成双链。敲除Alu元件会损害增强子-启动子环，而Alu插入或CRISPR-dCasRx介导的Alu与不受调控的启动子RNA的系联可在同源增强子上形成新的环。将535404个非编码风险变异映射回增强子-启动子RNA相互作用图谱，使其能够构建变异-功能图谱来解释它们的分子功能，包括11677个Alu元件中的15318个缺失或插入，并影响到6497个蛋白编码基因。研究人员进一步证明，PTK2增强子上的多态Alu插入可促进肿瘤发生。这项研究揭示了确定增强子-启动子配对特异性的原理，并提供了将非编码风险变异与其分子功能联系起来的框架。

附：英文原文

Title: Complementary Alu sequences mediate enhancer–promoter selectivity

Author: Liang, Liang, Cao, Changchang, Ji, Lei, Cai, Zhaokui, Wang, Di, Ye, Rong, Chen, Juan, Yu, Xiaohua, Zhou, Jie, Bai, Zhibo, Wang, Ruoyan, Yang, Xianguang, Zhu, Ping, Xue, Yuanchao

Issue&Volume: 2023-07-12

Abstract: Enhancers determine spatiotemporal gene expression programs by engaging with long-range promoters1,2,3,4. However, it remains unknown how enhancers find their cognate promoters. We recently developed a RNA in situ conformation sequencing technology to identify enhancer–promoter connectivity using pairwise interacting enhancer RNAs and promoter-derived noncoding RNAs5,6. Here we apply this technology to generate high-confidence enhancer–promoter RNA interaction maps in six additional cell lines. Using these maps, we discover that 37.9% of the enhancer–promoter RNA interaction sites are overlapped with Alu sequences. These pairwise interacting Alu and non-Alu RNA sequences tend to be complementary and potentially form duplexes. Knockout of Alu elements compromises enhancer–promoter looping, whereas Alu insertion or CRISPR–dCasRx-mediated Alu tethering to unregulated promoter RNAs can create new loops to homologous enhancers. Mapping 535,404 noncoding risk variants back to the enhancer–promoter RNA interaction maps enabled us to construct variant-to-function maps for interpreting their molecular functions, including 15,318 deletions or insertions in 11,677 Alu elements that affect 6,497 protein-coding genes. We further demonstrate that polymorphic Alu insertion at the PTK2 enhancer can promote tumorigenesis. Our study uncovers a principle for determining enhancer–promoter pairing specificity and provides a framework to link noncoding risk variants to their molecular functions.

DOI: 10.1038/s41586-023-06323-x

Source: https://www.nature.com/articles/s41586-023-06323-x