Mechanosensitive Endothelial METTL7A Regulates Internal m 7 G mRNA Methylation and Protects Against Atherosclerosis
Tzu-Pin Shentu, Tong Wu, Zhengjie Zhou, Jin Li, Chih-Fan Yeh, Jiayu Zhu, Ru-Ting Huang, Bernadette A. Miao, Brian Xi, Jason Lo, Lauryn Carver, Tzu-Han Lee, Lisheng Zhang, Devin Harrison, Chani J. Hodonsky, Gaelle Auguste, Uma Thanigai Arasu, Minna Kaikkonen-Määttä, Aliya N. Husain, Matthew V. Tirrell, Clint L. Miller, Bryan C. Dickinson, Kai-Chien Yang, Yun FangBACKGROUND:
Internal N7-methylguanosine (m 7 G) is a recently identified chemical modification of mammalian mRNA. Although the epitranscriptome plays a key role in regulating RNA metabolism and cellular function, the specific contribution of internal m 7 G to cardiovascular disease remains unknown. Atherosclerosis preferentially develops at sites of disturbed blood flow, which promotes endothelial activation; however, whether internal m 7 G regulates endothelial mechanotransduction and atherogenesis remains unclear.
METHODS:
We integrated epitranscriptomic profiling, human tissues, genetically modified mice, and targeted nanomedicine approaches to investigate the role of METTL7A (methyltransferase-like protein 7A), a putative internal m
7
G methyltransferase, in endothelial mechanobiology and atherosclerosis. Vascular endothelial cells were subjected to atheroprotective and atheroprone flow waveforms in vitro and in vivo. METTL7A function was assessed using RNA sequencing, liquid chromatography–tandem mass spectrometry, crosslinking immunoprecipitation sequencing, RNA stability assays, and a clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated–inspired RNA targeting system. METTL7A expression was examined in human coronary arteries with and without atherosclerosis. Atherosclerosis studies were conducted using global and endothelial-specific
RESULTS:
Atheroprotective unidirectional flow significantly induced METTL7A expression, which promoted internal m
7
G methylation of endothelial transcripts without affecting cap-associated m
7
G. METTL7A preferentially bound AG-enriched motifs in protein-coding mRNAs and increased internal m
7
G methylation and stability of
CONCLUSIONS:
METTL7A is a mechanosensitive internal m 7 G methyltransferase that maintains endothelial homeostasis by stabilizing the anti-inflammatory transcripts KLF4 (Krüppel-like factor 4) and NFKBIA. Loss of METTL7A disrupts endothelial function and accelerates atherogenesis. Endothelial restoration of METTL7A through complementary targeted nanoparticle platforms significantly reduces atherosclerotic burden. These findings uncover a novel epitranscriptomic mechanism governing vascular health and position METTL7A as a promising therapeutic target for atherosclerotic cardiovascular disease.