Semaphorin 6A phase separation sustains a histone lactylation–dependent lactate buildup in pathological angiogenesis
Abstract
Ischemic retinal diseases are major causes of blindness worldwide and are characterized by pathological angiogenesis. Epigenetic alterations in response to metabolic shifts in endothelial cells (ECs) suffice to underlie excessive angiogenesis. Lactate accumulation and its subsequent histone lactylation in ECs contribute to vascular disorders. However, the regulatory mechanism of establishing and sustaining lactylation modification remains elusive. Here, we showed that lactate accumulation induced histone lactylations on H3K9 and H3K18 in neovascular ECs in the proliferative stage of oxygen-induced retinopathy. Joint CUT&Tag and scRNA-seq analyses identified Prmt5 as a target of H3K9la and H3K18la in isolated retinal ECs. EC-specific deletion of Prmt5 since the early stage of revascularization suppressed a positive feedback loop of lactate production and histone lactylation, thus inhibiting neovascular tuft formation. Mechanistically, the C-terminal intrinsically disorder region (IDR) of the transmembrane semaphorin 6A (SEMA6A) forms liquid–liquid phase separation condensates to recruit RHOA and P300, facilitating P300 phosphorylation and histone lactylation cycle. Deletion of endothelial Sema6A reduced H3K9la and H3K18la at the promoter of PRMT5 and diminished its expression. The induction of histone lactylation by SEMA6A-IDR and its pro-angiogenic effect were abrogated by deletion of Prmt5 . Our study illustrates a sustainable histone lactylation machinery driven by phase separation-dependent lactyltransferase activation in dysregulated vascularization.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (18)
Ya Ma
School of Chemistry and Chemical Engineering
Zhuyi Zhang
Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Department of Toxicology, School of Public Health, Sun Yat-sen University
Xiaolian Cao
Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Department of Toxicology, School of Public Health, Sun Yat-sen University
Dianlei Guo
State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University
Shuting Huang
Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Department of Toxicology, School of Public Health, Sun Yat-sen University
Lijing Xie
State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University
Mingjuan Wu
State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University
Junru Li
Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Department of Toxicology, School of Public Health, Sun Yat-sen University
Chenxin Li
Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Department of Toxicology, School of Public Health, Sun Yat-sen University
Yu Chu
Research Center for Crystal Materials; CAS Key Laboratory of Functional Materials and Devices for Special Environmental Conditions; Xinjiang Key Laboratory of Functional Crystal Materials, Xinjiang Technical Institute of Physics & Chemistry, CAS, 40-1 South Beijing Road, Urumqi 830011, China
Shuxin Jiang
State Key Laboratory of Organometallic Chemistry and Shanghai-Hongkong Joint Laboratory in Chemical Synthesis, Shanghai Institute of Organic Chemistry
Yu Hao
Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Department of Toxicology, School of Public Health, Sun Yat-sen University
Can Wang
Xiali Zhong
Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Department of Toxicology, School of Public Health, Sun Yat-sen University
Rong Ju
State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University
Feng Zhang
Chunqiao Liu
State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University
Yanhong Wei
Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Department of Toxicology, School of Public Health, Sun Yat-sen University