FTO-dependent m6A modification of Plpp3 in circSCMH1-regulated vascular repair and functional recovery following stroke

Bin Li, Wen Xi, Ying Bai, Xue Liu, Yuan Zhang, Lu Li, Liang Bian, Chenchen Liu, Ying Tang, Ling Shen, Li Yang, Xiaochun Gu, Jian Xie, Zhongqiu Zhou, Yu Wang, Xiaoyu Yu, Jianhong Wang, Jie Chao (), Bing Han () and Honghong Yao ()
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Bin Li: Southeast University
Wen Xi: Southeast University
Ying Bai: Southeast University
Xue Liu: Southeast University
Yuan Zhang: Southeast University
Lu Li: Southeast University
Liang Bian: Southeast University
Chenchen Liu: Southeast University
Ying Tang: Southeast University
Ling Shen: Southeast University
Li Yang: Southeast University
Xiaochun Gu: Medical School of Southeast University
Jian Xie: Southeast University
Zhongqiu Zhou: Southeast University
Yu Wang: Southeast University
Xiaoyu Yu: Southeast University
Jianhong Wang: Chinese Academy of Sciences
Jie Chao: Southeast University
Bing Han: Southeast University
Honghong Yao: Southeast University

Nature Communications, 2023, vol. 14, issue 1, 1-19

Abstract: Abstract Vascular repair is considered a key restorative measure to improve long-term outcomes after ischemic stroke. N6-methyladenosine (m6A), the most prevalent internal modification in eukaryotic mRNAs, functionally mediates vascular repair. However, whether circular RNA SCMH1 (circSCMH1) promotes vascular repair by m6A methylation after stroke remains to be elucidated. Here, we identify the role of circSCMH1 in promoting vascular repair in peri-infarct cortex of male mice and male monkeys after photothrombotic (PT) stroke, and attenuating the ischemia-induced m6A methylation in peri-infarct cortex of male mice after PT stroke. Mechanically, circSCMH1 increased the translocation of ubiquitination-modified fat mass and obesity-associated protein (FTO) into nucleus of endothelial cells (ECs), leading to m6A demethylation of phospholipid phosphatase 3 (Plpp3) mRNA and subsequently the increase of Plpp3 expression in ECs. Our data demonstrate that circSCMH1 enhances vascular repair via FTO-regulated m6A methylation after stroke, providing insights into the mechanism of circSCMH1 in promoting stroke recovery.

Date: 2023
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DOI: 10.1038/s41467-023-36008-y

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