Liu Bei, Wu Tong, Miao Bernadette A, Ji Fei, Liu Shun, Wang Pingluan, Zhao Yutao, Zhong Yuhao, Sundaram Arunkumar, Zeng Tie-Bo, Majcherska-Agrawal Marta, Keenan Robert J, Pan Tao, He Chuan
Department of Chemistry, The University of Chicago, Chicago, IL 60637, USA; Howard Hughes Medical Institute, Chicago, IL 60637, USA.
Howard Hughes Medical Institute, Chicago, IL 60637, USA; Pritzker School of Molecular Engineering, The University of Chicago, Chicago, IL 60637, USA; Medical Scientist Training Program, The University of Chicago, Chicago, IL 60637, USA.
Cell. 2025 Jan 23;188(2):465-483.e22. doi: 10.1016/j.cell.2024.10.046. Epub 2024 Nov 22.
Small nucleolar RNAs (snoRNAs) are non-coding RNAs known for guiding RNA modifications, including 2'-O-methylation (N) and pseudouridine (Ψ). While snoRNAs may also interact with other RNAs, such as mRNA, the full repertoire of RNAs targeted by snoRNA remains elusive due to the lack of effective technologies that identify snoRNA targets transcriptome wide. Here, we develop a chemical crosslinking-based approach that comprehensively detects cellular RNA targets of snoRNAs, yielding thousands of previously unrecognized snoRNA-mRNA interactions in human cells and mouse brain tissues. Many interactions occur outside of snoRNA-guided RNA modification sites, hinting at non-canonical functions beyond RNA modification. We find that one of these snoRNAs, SNORA73, targets mRNAs that encode secretory proteins and membrane proteins. SNORA73 also interacts with 7SL RNA, part of the signal recognition particle (SRP) required for protein secretion. The mRNA-SNORA73-7SL RNA interactions enhance the association of the SNORA73-target mRNAs with SRP, thereby facilitating the secretion of encoded proteins.
小核仁RNA（snoRNAs）是一类非编码RNA，以指导RNA修饰而闻名，包括2'-O-甲基化（N）和假尿苷（Ψ）。虽然snoRNAs也可能与其他RNA相互作用，如mRNA，但由于缺乏全转录组范围内识别snoRNA靶标的有效技术，snoRNA靶向的RNA的完整目录仍然难以捉摸。在这里，我们开发了一种基于化学交联的方法，该方法全面检测snoRNAs的细胞RNA靶标，在人类细胞和小鼠脑组织中产生了数千种以前未被识别的snoRNA-mRNA相互作用。许多相互作用发生在snoRNA引导的RNA修饰位点之外，这暗示了RNA修饰之外的非经典功能。我们发现这些snoRNAs之一，SNORA73，靶向编码分泌蛋白和膜蛋白的mRNA。SNORA73还与7SL RNA相互作用，7SL RNA是蛋白质分泌所需的信号识别颗粒（SRP）的一部分。mRNA-SNORA73-7SL RNA相互作用增强了SNORA73靶向的mRNA与SRP的关联，从而促进了编码蛋白的分泌。
