The Hidden Role of Semaphorin 6A in Eye Diseases

Pathological angiogenesis is a major player in ischemic retinal diseases. These diseases are a leading cause of blindness globally. The process involves the growth of new, abnormal blood vessels. This happens due to changes in how genes are expressed in response to shifts in metabolism within endothelial cells. These are the cells that line blood vessels. Lactate buildup and the resulting histone lactylation in these cells are key factors in vascular disorders. Histone lactylation is a process where lactate, a byproduct of metabolism, attaches to histones, which are proteins that package DNA. This process can alter gene expression. However, the exact mechanisms that sustain this process are not fully understood. Researchers have found that lactate buildup leads to specific histone lactylations on H3K9 and H3K18 in neovascular endothelial cells. This occurs during the proliferative stage of oxygen-induced retinopathy. This is a condition where new blood vessels grow abnormally in the retina due to lack of oxygen. The study used advanced techniques to identify Prmt5 as a target of these lactylations in retinal endothelial cells. The deletion of Prmt5 in endothelial cells from the early stages of revascularization suppressed a feedback loop. This loop involves lactate production and histone lactylation, inhibiting the formation of neovascular tufts. These are abnormal clusters of new blood vessels. The study also revealed that the C-terminal intrinsically disordered region of semaphorin 6A forms liquid-like condensates. These condensates recruit RHOA and P300, facilitating the phosphorylation of P300 and the cycle of histone lactylation. The deletion of endothelial Sema6A reduced histone lactylation at the promoter of PRMT5, diminishing its expression. The induction of histone lactylation by SEMA6A-IDR and its pro-angiogenic effect were also stopped by the deletion of Prmt5. This research highlights a sustainable mechanism for histone lactylation. This mechanism is driven by phase separation-dependent lactyltransferase activation in abnormal vascularization. The findings suggest that targeting semaphorin 6A could be a potential strategy for treating ischemic retinal diseases. By understanding how semaphorin 6A contributes to pathological angiogenesis, researchers may develop new therapies to prevent blindness caused by these diseases. The study provides a critical look at the role of semaphorin 6A in vascular disorders. It offers new insights into the mechanisms that sustain histone lactylation in endothelial cells.