广东省肿瘤临床研究中心Jian Zheng和Dongxin Lin共同合作，近期取得重要工作进展，他们研究发现，超级增强子RNA m⁶A在胰腺导管腺癌中促进局部染色质可及性和癌基因转录。相关研究成果2023年11月13日在线发表于《自然—遗传学》杂志上。

据介绍，非编码RNA N⁶-甲基腺苷（m⁶A）修饰的生物学功能仍知之甚少。

研究人员描述了胰腺导管腺癌（PDAC）中超级增强子RNA（seRNA）m⁶A修饰的情况，并揭示了m⁶A-seRNA、H3K4me3修饰、染色质可及性和癌基因转录的调控轴。研究人员证明了在PDAC中过表达的辅因子家族蛋白CFL1是一种METTL3辅因子，有助于seRNA m⁶A甲基化的形成。增加的seRNA m⁶A被读取器YTHDC2识别，其募集H3K4甲基转移酶MLL1以共转录方式促进H3K4me3修饰。具有高水平H3K4me3的超级增强子增强染色质可及性并促进癌基因转录。

总之，这些结果揭示了CFL1–METTL3–seRNA m⁶A–YTHDC2/MLL1轴，该轴在局部染色质状态和基因表达的表观遗传学调控中发挥作用，这加强了人们对超级增强子及其转录物功能的了解。

附：英文原文

Title: Super-enhancer RNA m6A promotes local chromatin accessibility and oncogene transcription in pancreatic ductal adenocarcinoma

Author: Li, Rui, Zhao, Hongzhe, Huang, Xudong, Zhang, Jialiang, Bai, Ruihong, Zhuang, Lisha, Wen, Shujuan, Wu, Shaojia, Zhou, Quanbo, Li, Mei, Zeng, Lingxing, Zhang, Shaoping, Deng, Shuang, Su, Jiachun, Zuo, Zhixiang, Chen, Rufu, Lin, Dongxin, Zheng, Jian

Issue&Volume: 2023-11-13

Abstract: The biological functions of noncoding RNA N6-methyladenosine (m6A) modification remain poorly understood. In the present study, we depict the landscape of super-enhancer RNA (seRNA) m6A modification in pancreatic ductal adenocarcinoma (PDAC) and reveal a regulatory axis of m6A seRNA, H3K4me3 modification, chromatin accessibility and oncogene transcription. We demonstrate the cofilin family protein CFL1, overexpressed in PDAC, as a METTL3 cofactor that helps seRNA m6A methylation formation. The increased seRNA m6As are recognized by the reader YTHDC2, which recruits H3K4 methyltransferase MLL1 to promote H3K4me3 modification cotranscriptionally. Super-enhancers with a high level of H3K4me3 augment chromatin accessibility and facilitate oncogene transcription. Collectively, these results shed light on a CFL1–METTL3–seRNA m6A–YTHDC2/MLL1 axis that plays a role in the epigenetic regulation of local chromatin state and gene expression, which strengthens our knowledge about the functions of super-enhancers and their transcripts.

DOI: 10.1038/s41588-023-01568-8

Source: https://www.nature.com/articles/s41588-023-01568-8