Reprogramming of m6A epitranscriptome is crucial for shaping of transcriptome and proteome in response to hypoxia

作者：Wang, Yan-Jie; Yang, Bing; Lai, Qiao; Shi, Jun-Fang; Peng, Jiang-Yun; Zhang, Yin; Hu, Kai-Shun; Li, Ya-Qing; Peng, Jing-Wen; Yang, Zhi-Zhi; Li, Yao-Ting; Pan, Yue; Koeffler, H. Phillip; Liao, Jian-You^*; Yin, Dong^*

来源：RNA Biology, 2021, 18(1): 131-143.

DOI：10.1080/15476286.2020.1804697

• Hypoxia
• m(6)A epitranscriptome
• trancriptome
• proteome
• ATP production

Hypoxia causes a series of responses supporting cells to survive in harsh environments. Substantial post-transcriptional and translational regulation during hypoxia has been observed. However, detailed regulatory mechanism in response to hypoxia is still far from complete. RNA m(6)A modification has been proven to govern the life cycle of RNAs. Here, we reported that total m(6)A level of mRNAs was decreased during hypoxia, which might be mediated by the induction of m(6)A eraser, ALKBH5. Meanwhile, expression levels of most YTH family members of m(6)A readers were systematically down-regulated. Transcriptome-wide analysis of m(6)A revealed a drastic reprogramming of m(6)A epitranscriptome during cellular hypoxia. Integration of m(6)A epitranscriptome with either RNA-seq based transcriptome analysis or mass spectrometry (LC-MS/MS) based proteome analysis of cells upon hypoxic stress revealed that reprogramming of m(6)A epitranscriptome reshaped the transcriptome and proteome, thereby supporting efficient generation of energy for adaption to hypoxia. Moreover, ATP production was blocked when silencing an m(6)A eraser, ALKBH5, under hypoxic condition, demonstrating that m(6)A pathway is an important regulator during hypoxic response. Collectively, our studies indicate that crosstalk between m(6)A and HIF1 pathway is essential for cellular response to hypoxia, providing insights into the underlying molecular mechanisms during hypoxia.

• 单位
  中山大学; 南方医科大学