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Gli2-induced lncRNA Peg13 alleviates cerebral ischemia-reperfusion injury by suppressing Yy1 transcription in a PRC2 complex-dependent manner

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Abstract

Endothelial cell dysfunction plays an important role in cerebral ischemia-reperfusion (I/R) injury. LncRNA Peg13 is reported to be down-regulated in brain microvascular endothelial cells (BMVECs) induced by glucose-oxygen deprivation (OGD), but the mechanism of its involvement in I/R progression remains to be further explored. Here, mouse BMVECs (bEnd.3 cells) were treated with OGD / reoxygenation (OGD/R) to simulate I/R injury in vitro. Peg13 and Gli2 expression was decreased in OGD/R-treated bEnd.3 cells. And overexpression of Peg13 or Gli2 prevented OGD/R-induced reduction in cell migration and angiogenesis, as well as upregulation in cell apoptosis and oxidative stress levels. Mechanism exploration showed that Gli2 promoted the transcription of Peg13. And Peg13 repressed Yy1 transcription by binding to Ezh2 (a key subunit of PRC2 complex) and inducing the enrichment of H3K27me3 in Yy1 promoter region, thereby suppressing the transcriptional inhibition effect of Yy1 on Notch3 and promoting the expression of Notch3. Consistently, Notch3 overexpression hindered OGD/R-induced endothelium dysfunction. In addition, a brain I/R injury model was established using middle cerebral artery occlusion surgery. And lentivirus-mediated Gli2 and Peg13 overexpression vectors were injected into mice via the lateral ventricle one week before surgery. The results showed that overexpression of Peg13 or Gli2 alleviated I/R-induced neurological deficit, cerebral infarct and cerebral edema. And simultaneous overexpression of Peg13 and Gli2 showed a better protective effect than overexpression of Gli2 or Peg13 alone. In conclusion, Peg13 regulated by Gli2 inhibits Yy1 transcription in a PCR2 complex-dependent manner, and blocks the transcriptional repression of Notch3 by Yy1, thereby exerting neuroprotective effects on cerebral I/R injury.

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Data Availability

The datasets used during the present study are available from the corresponding author upon reasonable request.

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Authors and Affiliations

  1. Department of Neurology, the Second Affiliated Hospital of Xi’an Jiaotong University, No. 157 Xiwulu, 710004, Xi’an, Shaanxi province, China

    Yanling Li, Hong Fan, Yun Du, Ru Zhang, Shuqin Zhan, Guilian Zhang & Ning Bu

  2. Department of Geriatrics, the Second Affiliated Hospital of Xi’an Jiaotong University, Shaanxi province, China

    Chuntian Liu

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  1. Yanling Li
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  2. Chuntian Liu
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  3. Hong Fan
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  5. Ru Zhang
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Contributions

Yanling Li and Chuntian Liu conceived and designed research, performed experiments and wrote the manuscript. Hong Fan and Yun Du collected and analyzed the data. Ru Zhang and Shuqin Zhan contributed the methodology. Guilian Zhang and Ning Bu edited the manuscript. All authors reviewed the manuscript.

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Correspondence to Yanling Li.

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Li, Y., Liu, C., Fan, H. et al. Gli2-induced lncRNA Peg13 alleviates cerebral ischemia-reperfusion injury by suppressing Yy1 transcription in a PRC2 complex-dependent manner. Metab Brain Dis 38, 1389–1404 (2023). https://doi.org/10.1007/s11011-023-01159-w

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