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

Abstract

Background Ocular neovascularization is a leading cause of blindness. Retinal microglia have been implicated in hypoxia-induced angiogenesis and vasculopathy, but the underlying mechanisms are not entirely clear. Lactylation is a novel lactate-derived posttranslational modification that plays key roles in multiple cellular processes. Since hypoxia in ischemic retinopathy is a precipitating factor for retinal neovascularization, lactylation is very likely to be involved in this process. The present study aimed to explore the role of lactylation in retinal neovascularization and identify new therapeutic targets for retinal neovascular diseases. Results Microglial depletion by the colony-stimulating factor 1 receptor (CSF1R) inhibitor PLX3397 suppresses retinal neovascularization in oxygen-induced retinopathy. Hypoxia increased lactylation in microglia and accelerates FGF2 expression, promoting retinal neovascularization. We identify 77 sites of 67 proteins with increased lactylation in the context of increased lactate under hypoxia. Our results show that the nonhistone protein Yin Yang-1 (YY1), a transcription factor, is lactylated at lysine 183 (K183), which is regulated by p300. Hyperlactylated YY1 directly enhances FGF2 transcription and promotes angiogenesis. YY1 mutation at K183 eliminates these effects. Overexpression of p300 increases YY1 lactylation and enhances angiogenesis in vitro and administration of the p300 inhibitor A485 greatly suppresses vascularization in vivo and in vitro. Conclusions Our results suggest that YY1 lactylation in microglia plays an important role in retinal neovascularization by upregulating FGF2 expression. Targeting the lactate/p300/YY1 lactylation/FGF2 axis may provide new therapeutic targets for proliferative retinopathies.

YY1 Lactylation Aggravates Autoimmune Uveitis by Enhancing Microglial Functions via Inflammatory Genes

“…YY1, a transcription factor that regulates gene expression, [ 25 ] undergoes epigenetic modifications implicated in gene mediating. [ 30 , 35 , 36 ] In a study on chronic hepatitis, YY1 degradation via ubiquitination activated the HNF4 α/MiR‐122/CCL2 pathway, [ 35 ] while YY1 phosphorylation at S118 induced atherosclerosis. [ 36 ] Our previous study showed that YY1 lactylation contributed to elevated FGF2 expression.…”

“…[ 36 ] Our previous study showed that YY1 lactylation contributed to elevated FGF2 expression. [ 30 ] Building on these findings, CUT&Tag analysis was performed to identify the downstream target genes of YY1 lactylation. Briefly, HMC3 cells were divided into two groups: the control group was cultured in serum‐free EMEM and the experimental group was stimulated with LPS+IFN‐γ additionally for 24 h. Using CUT&Tag antibodies against YY1, we identified 29997 overlapped peaks between the two groups ( Figure 7 a ).…”

“…DCA was added at a concentration of 20 mM and Rotenone was added at a concentration of 50 nM, according to previous studies. [30] Isolation of Primary Microglia: Postnatal (1-7 days) C57BL/6J mice were sacrificed. Brains were harvested, cut into pieces, and digested using trypsin for 30 min at 37 °C.…”

“…[ 29 ] Additionally, our previous study demonstrated that YY1 lactylation in microglia activated fibroblast growth factor 2 （FGF2） expression, consequently promoting pathological angiogenesis in retinopathy of prematurity (ROP). [ 30 ] However, the connection between YY1 lactylation and AU remains unclear.…”

Histone lactylation bridges metabolic reprogramming and epigenetic rewiring in driving carcinogenesis: Oncometabolite fuels oncogenic transcription

“…19 Thus far, the importance of histone lactylation in facilitating metabolic rewiring, altering the immunological environment, controlling cell destiny and impacting cancer stem-ness and senescence has been discovered (Figure 3 and Table 1). [92][93][94]…”