ASF1A-dependent P300-mediated histone H3 lysine 18 lactylation promotes atherosclerosis by regulating EndMT

• Published in: Acta pharmaceutica Sinica. B Vol. 14; no. 7; pp. 3027 - 3048
• Main Authors: Dong, Mengdie, Zhang, Yunjia, Chen, Minghong, Tan, Yongkang, Min, Jiao, He, Xian, Liu, Fuhao, Gu, Jiaming, Jiang, Hong, Zheng, Longbin, Chen, Jiajing, Yin, Quanwen, Li, Xuesong, Chen, Xiang, Shao, Yongfeng, Ji, Yong, Chen, Hongshan
• Format: Journal Article
• Language: English
• Published: Elsevier B.V 01.07.2024; Elsevier
• Subjects: ASF1A; Atherosclerosis; Endothelial dysfunction; Endothelial-to-mesenchymal transition; Epigenetic; Histone lactylation; Lactate; Original; SNAI1; Lactate; Histone lactylation; Atherosclerosis; SNAI1; Endothelial dysfunction; Endothelial-to-mesenchymal transition; Epigenetic; ASF1A
• ISSN: 2211-3835; 2211-3843
• DOI: 10.1016/j.apsb.2024.03.008

Endothelial-to-mesenchymal transition (EndMT) is a key driver of atherosclerosis. Aerobic glycolysis is increased in the endothelium of atheroprone areas, accompanied by elevated lactate levels. Histone lactylation, mediated by lactate, can regulate gene expression and participate in disease regulation. However, whether histone lactylation is involved in atherosclerosis remains unknown. Here, we report that lipid peroxidation could lead to EndMT-induced atherosclerosis by increasing lactate-dependent histone H3 lysine 18 lactylation (H3K18la) in vitro and in vivo, as well as in atherosclerotic patients’ arteries. Mechanistically, the histone chaperone ASF1A was first identified as a cofactor of P300, which precisely regulated the enrichment of H3K18la at the promoter of SNAI1, thereby activating SNAI1 transcription and promoting EndMT. We found that deletion of ASF1A inhibited EndMT and improved endothelial dysfunction. Functional analysis based on ApoeKOAsf1aECKO mice in the atherosclerosis model confirmed the involvement of H3K18la in atherosclerosis and found that endothelium-specific ASF1A deficiency inhibited EndMT and alleviated atherosclerosis development. Inhibition of glycolysis by pharmacologic inhibition and advanced PROTAC attenuated H3K18la, SNAI1 transcription, and EndMT-induced atherosclerosis. This study illustrates precise crosstalk between metabolism and epigenetics via H3K18la by the P300/ASF1A molecular complex during EndMT-induced atherogenesis, which provides emerging therapies for atherosclerosis. Histone chaperone ASF1A and P300 together regulate histone H3 lysine 18 lactylation, which increases the expression of the endothelial-to-mesenchymal transition transcription factor SNAI1, inducing endothelial dysfunction and promoting atherosclerosis. [Display omitted]