Huang Xiang, Zhang Jie, Cun Yixian, Ye Meijun, Ren Zhijun, Guo Wenbing, Ma Xiaojun, Liu Jiayin, Luo Weiwei, Sun Xiang, Shao Jingwen, Wu Zehong, Zhu Xiaofeng, Wang Jinkai
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.
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.
Mol Cell. 2025 Apr 3;85(7):1349-1365.e10. doi: 10.1016/j.molcel.2025.02.016. Epub 2025 Mar 17.
Interaction between the N-methyladenosine (mA) methyltransferase METTL3 and METTL14 is critical for METTL3 to deposit mA on various types of RNAs. It remains to be uncovered whether there is spatial control of mA 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 mA 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 mA on enhancer and promoter RNAs.
N-甲基腺苷（mA）甲基转移酶METTL3与METTL14之间的相互作用对于METTL3在各种类型RNA上沉积mA至关重要。目前尚不清楚在不同类型RNA上的mA沉积是否存在空间控制。在这里，通过在A549细胞系中进行全基因组CRISPR-Cas9筛选，我们发现H3K27ac乙酰转移酶p300介导的METTL3乙酰化通过抑制其与METTL14的相互作用来抑制METTL3与H3K27ac标记的染色质的结合。一致地，催化METTL3乙酰化的p300特异性地发生在H3K27ac标记的染色质上。METTL3乙酰化位点的破坏性突变选择性地促进来自以H3K27ac标记的p300结合增强子和启动子的染色质相关RNA的mA，导致铁死亡抑制相关基因的转录抑制。此外，PAK2通过磷酸化METTL3促进METTL3乙酰化。抑制PAK2以依赖于METTL3乙酰化的方式促进铁死亡。我们的研究揭示了一种空间选择性方式，可特异性调节mA在增强子和启动子RNA上的沉积。
