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 pla...
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| Format: | Article |
| Language: | English |
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BMC
2023-04-01
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| Series: | Genome Biology |
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| Online Access: | https://doi.org/10.1186/s13059-023-02931-y |
| _version_ | 1797841007551709184 |
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| author | Xiaotang Wang Wei Fan Na Li Yan Ma Mudi Yao Guoqing Wang Siyuan He Wanqian Li Jun Tan Qi Lu Shengping Hou |
| author_facet | Xiaotang Wang Wei Fan Na Li Yan Ma Mudi Yao Guoqing Wang Siyuan He Wanqian Li Jun Tan Qi Lu Shengping Hou |
| author_sort | Xiaotang Wang |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-09T16:23:55Z |
| format | Article |
| id | doaj.art-6edda95ad7c649a7b8fae15db2ce7b3f |
| institution | Directory Open Access Journal |
| issn | 1474-760X |
| language | English |
| last_indexed | 2024-04-09T16:23:55Z |
| publishDate | 2023-04-01 |
| publisher | BMC |
| record_format | Article |
| series | Genome Biology |
| spelling | doaj.art-6edda95ad7c649a7b8fae15db2ce7b3f2023-04-23T11:19:06ZengBMCGenome Biology1474-760X2023-04-0124112310.1186/s13059-023-02931-yYY1 lactylation in microglia promotes angiogenesis through transcription activation-mediated upregulation of FGF2Xiaotang Wang0Wei Fan1Na Li2Yan Ma3Mudi Yao4Guoqing Wang5Siyuan He6Wanqian Li7Jun Tan8Qi Lu9Shengping Hou10The First Affiliated Hospital of Chongqing Medical UniversityThe First Affiliated Hospital of Chongqing Medical UniversitySchool of Basic Medical Sciences, Chongqing Medical UniversityThe Affiliated Eye Hospital, Nanjing Medical UniversityThe Affiliated Eye Hospital, Nanjing Medical UniversityThe First Affiliated Hospital of Chongqing Medical UniversityThe First Affiliated Hospital of Chongqing Medical UniversityThe First Affiliated Hospital of Chongqing Medical UniversityThe First Affiliated Hospital of Chongqing Medical UniversityThe Children’s Hospital of Chongqing Medical UniversityThe First Affiliated Hospital of Chongqing Medical UniversityAbstract 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.https://doi.org/10.1186/s13059-023-02931-yAngiogenesisRetinal microgliaPosttranslational modifications (PTMs)LactylationYY1 |
| spellingShingle | Xiaotang Wang Wei Fan Na Li Yan Ma Mudi Yao Guoqing Wang Siyuan He Wanqian Li Jun Tan Qi Lu Shengping Hou YY1 lactylation in microglia promotes angiogenesis through transcription activation-mediated upregulation of FGF2 Genome Biology Angiogenesis Retinal microglia Posttranslational modifications (PTMs) Lactylation YY1 |
| title | YY1 lactylation in microglia promotes angiogenesis through transcription activation-mediated upregulation of FGF2 |
| title_full | YY1 lactylation in microglia promotes angiogenesis through transcription activation-mediated upregulation of FGF2 |
| title_fullStr | YY1 lactylation in microglia promotes angiogenesis through transcription activation-mediated upregulation of FGF2 |
| title_full_unstemmed | YY1 lactylation in microglia promotes angiogenesis through transcription activation-mediated upregulation of FGF2 |
| title_short | YY1 lactylation in microglia promotes angiogenesis through transcription activation-mediated upregulation of FGF2 |
| title_sort | yy1 lactylation in microglia promotes angiogenesis through transcription activation mediated upregulation of fgf2 |
| topic | Angiogenesis Retinal microglia Posttranslational modifications (PTMs) Lactylation YY1 |
| url | https://doi.org/10.1186/s13059-023-02931-y |
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