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.

非编码RNA N ⁶ -甲基腺苷(m ⁶ A) 修饰的生物学功能仍然知之甚少。在本研究中，我们描绘了胰腺导管腺癌 (PDAC) 中超级增强子 RNA (seRNA) m ⁶ A 修饰的情况，并揭示了 m ⁶ A seRNA 的调控轴、H3K4me3 修饰、染色质可及性和癌基因转录。我们证明了在 PDAC 中过表达的丝切蛋白家族蛋白 CFL1 作为 METTL3 辅助因子，有助于 seRNA m ⁶ A 甲基化形成。增加的seRNA m ⁶ As 被阅读器YTHDC2 识别，它招募H3K4 甲基转移酶MLL1 来促进H3K4me3 共转录修饰。具有高水平 H3K4me3 的超级增强子可增强染色质可及性并促进癌基因转录。总的来说，这些结果揭示了 CFL1–METTL3–seRNA m ⁶ A–YTHDC2/MLL1 轴在局部染色质状态和基因表达的表观遗传调控中发挥的作用，这增强了我们对超级增强子及其功能的了解。成绩单。