Epigenetic ALYREF/UHRF1/RHOB Axis in Corneal Wound Healing and Implications for Epithelial Tumorigenesis

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Purpose: Corneal epithelial wound healing (CEWH) is a complex process influenced by epigenetic regulation. Ubiquitin-like with plant homeodomain (PHD) and ring finger domains 1 (UHRF1), it plays a key role in integrating epigenetic signals. However, its precise function in modulating CEWH remains poorly understood. We describe here the functional mechanisms of UHRF1 in modulating CEWH. Methods: Quantitative Reverse Transcription PCR (RT-qPCR), immunofluorescence, and gene manipulation were used to investigate UHRF1 expression patterns and functions during CEWH. Integrated multi-omics and targeted bisulfite sequencing (TBS) were performed to reveal the downstream target of UHRF1. Mutation assay was used to examine whether Aly/REF export factor (ALYREF) can recognize and bind RNA m5C-UHRF1. Gene expression profiling interactive analysis (GEPIA) was utilized to validate the correlation of UHRF1 with its upstream and downstream targets. Results: In this study, we demonstrate that UHRF1 enhances CEWH and sustains DNA methylation during CEWH, which is essential for this effect. A multi-omics analysis identified Ras homolog family member B (RHOB) as a downstream target of UHRF1. Our findings further revealed that UHRF1 epigenetically downregulates RHOB, thereby facilitating CEWH. Moreover, we showed that ALYREF binds to m5C sites on UHRF1 mRNA and enhances its translation. Finally, our analysis of molecular alterations and the clinical significance of ALYREF, UHRF1, and RHOB expression suggests that this epigenetic axis is also relevant in epithelial-derived tumors, which represent approximately 90% of all tumors. Conclusions: Our study identifies a novel epigenetic ALYREF/UHRF1/RHOB axis that enhances CEWH. Importantly, this axis appears to be conserved across various epithelial-derived tumors, suggesting its broader biological significance.

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