2. Academic Validation
  3. Spatial control of m6A deposition on enhancer and promoter RNAs through co-acetylation of METTL3 and H3K27 on chromatin

Spatial control of m6A deposition on enhancer and promoter RNAs through co-acetylation of METTL3 and H3K27 on chromatin

  • Mol Cell. 2025 Mar 11:S1097-2765(25)00147-9. doi: 10.1016/j.molcel.2025.02.016.
Xiang Huang 1,  Jie Zhang 2,  Yixian Cun 2,  Meijun Ye 2,  Zhijun Ren 1,  Wenbing Guo 1,  Xiaojun Ma 2,  Jiayin Liu 2,  Weiwei Luo 3,  Xiang Sun 2,  Jingwen Shao 2,  Zehong Wu 2,  Xiaofeng Zhu 4,  Jinkai Wang 5
Affiliations

Affiliations

  • 1 Department of Histoembryology and Cell Biology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China; Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-sen University, Guangzhou 510080, China; Medical College of Jiaying University, Meizhou 514031, China.
  • 2 Department of Histoembryology and Cell Biology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China; Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-sen University, Guangzhou 510080, China.
  • 3 GeneMind Biosciences Company Limited, Shenzhen 518000, China.
  • 4 State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 518000, China.
  • 5 Department of Histoembryology and Cell Biology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China; Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-sen University, Guangzhou 510080, China. Electronic address: wangjk@mail.sysu.edu.cn.
PMID: 40101711 DOI: 10.1016/j.molcel.2025.02.016
Abstract

Interaction between the N6-methyladenosine (m6A) methyltransferase METTL3 and METTL14 is critical for METTL3 to deposit m6A on various types of RNAs. It remains to be uncovered whether there is spatial control of m6A deposition on different types of RNAs. Here, through genome-wide CRISPR-Cas9 screening in the A549 cell line, we find that H3K27ac acetylase p300-mediated METTL3 acetylation suppresses the binding of METTL3 on H3K27ac-marked chromatin by inhibiting its interaction with METTL14. Consistently, p300 catalyzing the acetylation of METTL3 specifically occurs on H3K27ac-marked chromatin. Disruptive mutations on METTL3 acetylation sites selectively promote the m6A of chromatin-associated RNAs from p300-bound enhancers and promoters marked by H3K27ac, resulting in transcription inhibition of ferroptosis-inhibition-related genes. In addition, PAK2 promotes METTL3 acetylation by phosphorylating METTL3. Inhibition of PAK2 promotes Ferroptosis in a manner that depends on the acetylation of METTL3. Our study reveals a spatial-selective way to specifically regulate the deposition of m6A on enhancer and promoter RNAs.

Keywords

H3K27ac; METTL3; PAK2; chromatin-associated RNA; m(6)A; p300.

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