Nature Communications (Oct 2023)

CSTF2 mediated mRNA N 6-methyladenosine modification drives pancreatic ductal adenocarcinoma m6A subtypes

  • Yanfen Zheng,
  • Xingyang Li,
  • Shuang Deng,
  • Hongzhe Zhao,
  • Ying Ye,
  • Shaoping Zhang,
  • Xudong Huang,
  • Ruihong Bai,
  • Lisha Zhuang,
  • Quanbo Zhou,
  • Mei Li,
  • Jiachun Su,
  • Rui Li,
  • Xiaoqiong Bao,
  • Lingxing Zeng,
  • Rufu Chen,
  • Jian Zheng,
  • Dongxin Lin,
  • Chuan He,
  • Jialiang Zhang,
  • Zhixiang Zuo

DOI
https://doi.org/10.1038/s41467-023-41861-y
Journal volume & issue
Vol. 14, no. 1
pp. 1 – 17

Abstract

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Abstract N 6 -methyladenosine (m6A) modification of gene transcripts plays critical roles in cancer. Here we report transcriptomic m6A profiling in 98 tissue samples from 65 individuals with pancreatic ductal adenocarcinoma (PDAC). We identify 17,996 m6A peaks with 195 hyper-methylated and 93 hypo-methylated in PDAC compared with adjacent normal tissues. The differential m6A modifications distinguish two PDAC subtypes with different prognosis outcomes. The formation of the two subtypes is driven by a newly identified m6A regulator CSTF2 that co-transcriptionally regulates m6A installation through slowing the RNA Pol II elongation rate during gene transcription. We find that most of the CSTF2-regulated m6As have positive effects on the RNA level of host genes, and CSTF2-regulated m6As are mainly recognized by IGF2BP2, an m6A reader that stabilizes mRNAs. These results provide a promising PDAC subtyping strategy and potential therapeutic targets for precision medicine of PDAC.