Isoform characterization of m6A in single cells identifies its role in RNA surveillance

Zhijun Ren, Jialiang He, Xiang Huang, Yan Gao, Chuanchuan Wei, Zehong Wu, Wenbing Guo, Feng Wang, Qingquan Zhao, Xiang Sun, Jie Zhang, Nan Cao, Lan Lin (), Jinkai Wang () and Yixian Cun ()
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Zhijun Ren: Sun Yat-sen University
Jialiang He: Sun Yat-sen University
Xiang Huang: Sun Yat-sen University
Yan Gao: Sun Yat-sen University
Chuanchuan Wei: Sun Yat-sen University
Zehong Wu: Sun Yat-sen University
Wenbing Guo: Sun Yat-sen University
Feng Wang: Children’s Hospital of Philadelphia
Qingquan Zhao: Sun Yat-Sen University
Xiang Sun: Sun Yat-sen University
Jie Zhang: Sun Yat-sen University
Nan Cao: Sun Yat-sen University
Lan Lin: Children’s Hospital of Philadelphia
Jinkai Wang: Sun Yat-sen University
Yixian Cun: Sun Yat-sen University

Nature Communications, 2025, vol. 16, issue 1, 1-19

Abstract: Abstract The distribution of m6A across various RNA isoforms and its heterogeneity within single cells are still not well understood. Here, we develop m6A-isoSC-seq, which employs both Oxford Nanopore long-read and Illumina short-read sequencing on the same 10x Genomics single-cell cDNA library with APOBEC1-YTH induced C-to-U mutations near m6A sites. Through m6A-isoSC-seq on a pooled sample of three cell line origins, we unveil a profound degree of m6A heterogeneity at both the isoform and single-cell levels. Through comparisons across single cells, we identify widespread specific m6A methylation on certain RNA isoforms, usually those misprocessed RNA isoforms. Compared to the coding isoforms of the same genes, the expression of highly methylated misprocessed RNA isoforms is more sensitive to METTL3 depletion. These misprocessed RNAs tend to have excessive m6A sites in coding regions, which are targets of CDS-m6A decay (CMD). This study offers undocumented insights into the role of m6A in RNA surveillance.

Date: 2025
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DOI: 10.1038/s41467-025-60869-0

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