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

作者：Xiang Huang, Jie Zhang, Yixian Cun, Meijun Ye, Zhijun Ren, Wenbing Guo, Xiaojun Ma, Jiayin Liu, Weiwei Luo, Xiang Sun, Jingwen Shao, Zehong Wu, Xiaofeng Zhu, Jinkai Wang · 发表于：Molecules and Cells · 年份：2025 · DOI：10.1016/j.molcel.2025.02.016 · 研究领域：Medicine

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.