美国肯塔基大学Mark T. W. Ebbert团队近期取得重要工作进展，他们研究利用深度长读RNA测序技术绘制老年人额叶皮层医学相关RNA异构体多样性图谱。相关研究成果2024年5月22日在线发表于《自然—生物技术》杂志上。

据介绍，确定来自医学相关基因的RNA异构体是否具有不同的功能可以促进RNA异构体的直接靶向用于疾病治疗。

为实现神经系统疾病的治疗目标，研究人员对12个死后老年人类额叶皮层（6例阿尔茨海默病病例和6例对照；50%为女性）进行了测序，每个样本使用一个Oxford Nanopore PromethION流动细胞。研究人员鉴定了1917个在额叶皮层表达多种异构体的医学相关基因，其中1018个具有不同蛋白质编码序列的多种异构体。

在这1018个基因中，57个与大脑相关疾病有关，包括严重抑郁症、精神分裂症、帕金森病和阿尔茨海默病。研究人员还发现医学相关基因中的53种新的RNA亚型，其中一些新亚型是该基因表达最高的亚型之一。他们还报道了五种线粒体编码的剪接RNA亚型。

总之，研究人员在阿尔茨海默病患者和对照组之间发现了99种差异表达的RNA异构体。

附：英文原文

Title: Mapping medically relevant RNA isoform diversity in the aged human frontal cortex with deep long-read RNA-seq

Author: Aguzzoli Heberle, Bernardo, Brandon, J. Anthony, Page, Madeline L., Nations, Kayla A., Dikobe, Ketsile I., White, Brendan J., Gordon, Lacey A., Fox, Grant A., Wadsworth, Mark E., Doyle, Patricia H., Williams, Brittney A., Fox, Edward J., Shantaraman, Anantharaman, Ryten, Mina, Goodwin, Sara, Ghiban, Elena, Wappel, Robert, Mavruk-Eskipehlivan, Senem, Miller, Justin B., Seyfried, Nicholas T., Nelson, Peter T., Fryer, John D., Ebbert, Mark T. W.

Issue&Volume: 2024-05-22

Abstract: Determining whether the RNA isoforms from medically relevant genes have distinct functions could facilitate direct targeting of RNA isoforms for disease treatment. Here, as a step toward this goal for neurological diseases, we sequenced 12 postmortem, aged human frontal cortices (6 Alzheimer disease cases and 6 controls; 50% female) using one Oxford Nanopore PromethION flow cell per sample. We identified 1,917 medically relevant genes expressing multiple isoforms in the frontal cortex where 1,018 had multiple isoforms with different protein-coding sequences. Of these 1,018 genes, 57 are implicated in brain-related diseases including major depression, schizophrenia, Parkinson’s disease and Alzheimer disease. Our study also uncovered 53 new RNA isoforms in medically relevant genes, including several where the new isoform was one of the most highly expressed for that gene. We also reported on five mitochondrially encoded, spliced RNA isoforms. We found 99 differentially expressed RNA isoforms between cases with Alzheimer disease and controls.

DOI: 10.1038/s41587-024-02245-9

Source: https://www.nature.com/articles/s41587-024-02245-9