YY1 lactylation in microglia promotes angiogenesis through transcription activation-mediated upregulation of FGF2

Abstract

Ocular neovascularization is a leading cause of blindness. Retinal microglia have been implicated in hypoxia-induced angiogenesis and vasculopathy, but the underlying mechanisms remain largely unknown. Here, we report that lactylation in microglia is critical for retinal neovascularization. Using lactylome and proteomic analyses, we identified a list of hyperlactylated proteins in the context of increased lactate under hypoxia. Yin Yang-1 (YY1), a transcription factor, is lactylated at lysine 183 (K183) under hypoxia, which is regulated by p300. Furthermore, hyperlactylated YY1 directly enhances fibroblast growth factor 2 (FGF2) transcription and promotes angiogenesis. YY1 mutation at K183 eliminates these effects. Notably, clinical retrospective analysis shows that lactate concentrations in retinopathy of prematurity (ROP) infants are significantly increased compared with those in controls. Taken together, our results demonstrate that YY1 lactylation in microglia promotes FGF2 expression and plays a pivotal proangiogenic role, providing new insights into retinal neovascular diseases.

Post-translational protein lactylation modification in health and diseases: a double-edged sword

“…YY1 is directly bound to the promoter of FGF2 and promotes the transcription of FGF2 through its high lactylation, thus promoting the formation of neovascularization. This situation is reversed by the p300/CBP inhibitor A-485 [110].…”

“…In addition to those above, lactate-induced lactylation can additionally contribute to DNA repair, embryo implantation, and the improvement of the fatty liver, but it can also lead to the worsening of pulmonary hypertension and proliferative retinopathies [105][106][107][108][109][110]. Sun Y et al [105] found that hyperlactylation of PARP1 regulated its ADP-ribosylation activity and might contribute to DNA repair based on an alkynyl-functionalized bioorthogonal chemical reporter, YnLac.…”

“…Generally, research suggests that lactylation in different cell types functions differently in different conditions. Non-histone YY1 with hyperlactylation regulated by the "writer" p300 in retinal microglia under hypoxia directly interacts with the promoter of FGF2 and promotes its transcription, thereby activating neovascularization [110]. Moreover, lactylation histone H3 is reported to associate with endometrial cells, oocytes, and embryonic cells and contributes to the maintenance of glutathionebased redox homeostasis and apoptotic balance, which are essential for successful embryo implantation [106,107].…”

New mechanisms: From lactate to lactylation to rescue heart failure

“…Thirdly, studying the correlation between lactylation and other modifications linked to heart disease and its regulatory mechanism would enhance understanding of the etiology of the disease. Finally, investigating the involvement of lactylation in various tissues and diseases can enhance our comprehension and potential utilisation of this process (7,8).…”

YY1 lactylation in microglia promotes angiogenesis through transcription activation-mediated upregulation of FGF2

“…The raw and processed proteomic and lactylome data are available in the Proteomics Identification Database with accession number PXD028737 [62]. All microscopy images are available at Figshare repositor [63]. All the other data generated in this study are included in the article and the Additional files.…”