Genome Med|中山大学肿瘤中心郑健团队揭示胰腺癌circRNA m6A修饰全基因组鉴定与表征

2022年8月4日 0条评论 732次阅读 0人点赞

最新细胞功能及机制文献分享

N⁶-甲基腺苷（m⁶A）修饰是真核细胞中最丰富的一种RNA修饰，其在癌症中发挥重要作用。目前，大多数相关研究都集中在线性RNA中的m⁶A修饰，对肿瘤中circRNA m6A修饰的探索仍然缺乏。2021年11月19日，中山大学肿瘤中心郑健团队在Genome Medicine上发表了题为“Genome-wide identification and characterization of circular RNA m⁶A modification in pancreatic cancer”的研究论文。在本研究中，团队为了检测circRNA中的m⁶A修饰，开发了一种新的生物信息学工具Circm6A（比现有的circRNA识别工具表现更好），将其应用于58例胰腺导管腺癌（PDAC）患者的77个组织样本的m⁶A-seq数据，描述了PDAC患者的m⁶A-circRNAs基因组景观，进一步弥补m⁶A修饰和circRNAs领域之间的知识鸿沟，并揭示了m⁶A-circRNAs在胰腺癌中的新角色。

PDAC是一种侵袭性肿瘤，通常在晚期被诊断出来，并将在这十年内成为癌症死亡的第二大原因，迄今为止，仍然没有有效的方法来治疗PDAC。高通量m⁶A RNA免疫沉淀测序（MeRIP-seq）研究表明，m⁶A修饰主要发生在具有共有基序“RRm6ACH”的信使RNA（mRNA）中。近年来的研究发现，circRNA是一类特殊的RNA，由5’和3’末端之间的共价连接产生，circRNA的失调在癌症进展中起着关键作用。虽然大多数m⁶A研究集中在mRNA，但一些研究表明m⁶A修饰也发生在circRNA中，其可影响circRNA的翻译效率。

在这项研究中，团队提出了一种称为“Circm6A”的算法来检测MeRIP-seq数据库中的circRNA m⁶A修饰。通过对患者的53个肿瘤和24个相邻正常组织样本的总RNA进行m⁶A-seq，并将Circm6A应用于m⁶A-seq数据。结果发现，团队从m⁶A-seq数据中共鉴定了8807个m⁶A-circRNA，与正常组织相比，PDAC肿瘤组织中m⁶A-circRNA倾向于高甲基化；而高甲基化的m⁶A-circRNA不仅与circRNA-mRNA共表达网络的显著增加相关，还会促进circRNA的循环化和翻译，最终导致许多重要的癌症相关通路失调。

《Genome Med|中山大学肿瘤中心郑健团队揭示胰腺癌circRNA m6A修饰全基因组鉴定与表征》

图 Circm6A框架示意图。Circm6A流程包括两个步骤：1）依据PCC和PEM信号从MeRIP-seq IP和INPUT样本中识别circRNA；2）比较线性转录本中circRNA或区域是否在IP样本显著富集（与MeRIP-seq数据中的INPUT样本相比），鉴定具有m⁶A修饰的circRNA和线性转录本。

期刊及DOI号

Genome Med. 2021 Nov 19.

doi: 10.1186/s13073-021-01002-w.

题目

Genome-wide identification and characterization of circular RNA m⁶A modification in pancreatic cancer

摘要

背景：N⁶-methyladenosine (m⁶A) is the most abundant modification of RNA in eukaryotic cells and play critical roles in cancer. While most related studies focus on m⁶A modifications in linear RNA, transcriptome-wide profiling and exploration of m⁶A modification in circular RNAs in cancer is still lacking.

方法：For the detection of m⁶A modification in circRNAs, we developed a new bioinformatics tools called Circm6A and applied it to the m⁶A-seq data of 77 tissue samples from 58 individuals with pancreatic ductal adenocarcinoma (PDAC).

结果：Circm6A performs better than the existing circRNA identification tools, which achieved highest F1 score among these tools in the detection of circRNAs with m⁶A modifications. By using Circm6A, we identified a total of 8807 m⁶A-circRNAs from our m⁶A-seq data. The m⁶A-circRNAs tend to be hypermethylated in PDAC tumor tissues compared with normal tissues. The hypermethylated m⁶A-circRNAs were associated with a significant gain of circRNA-mRNA coexpression network, leading to the dysregulation of many important cancer-related pathways. Moreover, we found the cues that hypermethylated m⁶A-circRNAs may promote the circularization and translation of circRNAs.

结论：These comprehensive findings further bridged the knowledge gaps between m⁶A modification and circRNAs fields by depicting the m⁶A-circRNAs genomic landscape of PDAC patients and revealed the emerging roles played by m⁶A-circRNAs in pancreatic cancer. Circm6A is available at https://github.com/canceromics/circm6a.

关键词：m⁶A modification, Circular RNA, m⁶A-seq, Pancreatic cancer