Multi-omics profiling of retinal pigment epithelium reveals enhancer-driven activation of RANK-NFATc1 signaling in traumatic proliferative vitreoretinopathy

Mengyu Liao, Xu Zhu, Yumei Lu, Xiaoping Yi, Youhui Hu, Yumeng Zhao, Zhisheng Ye, Xu Guo, Minghui Liang, Xin Jin, Hong Zhang, Xiaohong Wang, Ziming Zhao (), Yupeng Chen () and Hua Yan ()
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Mengyu Liao: Tianjin Medical University
Xu Zhu: Tianjin Medical University
Yumei Lu: Tianjin Medical University
Xiaoping Yi: Tianjin Medical University
Youhui Hu: Xuzhou Medical University
Yumeng Zhao: Tianjin Medical University
Zhisheng Ye: Tianjin Medical University
Xu Guo: Tianjin Medical University
Minghui Liang: Tianjin Medical University
Xin Jin: The First Affiliated Hospital of Harbin Medical University
Hong Zhang: The First Affiliated Hospital of Harbin Medical University
Xiaohong Wang: Tianjin Medical University
Ziming Zhao: Xuzhou Medical University
Yupeng Chen: Tianjin Medical University
Hua Yan: Tianjin Medical University

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: Abstract During the progression of proliferative vitreoretinopathy (PVR) following ocular trauma, previously quiescent retinal pigment epithelial (RPE) cells transition into a state of rapid proliferation, migration, and secretion. The elusive molecular mechanisms behind these changes have hindered the development of effective pharmacological treatments, presenting a pressing clinical challenge. In this study, by monitoring the dynamic changes in chromatin accessibility and various histone modifications, we chart the comprehensive epigenetic landscape of RPE cells in male mice subjected to traumatic PVR. Coupled with transcriptomic analysis, we reveal a robust correlation between enhancer activation and the upregulation of the PVR-associated gene programs. Furthermore, by constructing transcription factor regulatory networks, we identify the aberrant activation of enhancer-driven RANK-NFATc1 pathway as PVR advanced. Importantly, we demonstrate that intraocular interventions, including nanomedicines inhibiting enhancer activity, gene therapies targeting NFATc1 and antibody therapeutics against RANK pathway, effectively mitigate PVR progression. Together, our findings elucidate the epigenetic basis underlying the activation of PVR-associated genes during RPE cell fate transitions and offer promising therapeutic avenues targeting epigenetic modulation and the RANK-NFATc1 axis for PVR management.

Date: 2024
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DOI: 10.1038/s41467-024-51624-y

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