Abstract
The complex transcriptional regulatory network leads to the poor prognosis of glioma. The role of orphan CpG islands (oCGIs) in the transcriptional regulatory network has been overlooked. We conducted a comprehensive exploration of the cis-regulatory roles of oCGIs and enhancers by integrating multi-omics data. Direct regulation of target genes by oCGIs or enhancers is of great importance in the cis-regulatory network. Furthermore, based on single-cell multi-omics data, we found that the highly activated cis-regulatory network in cluster 2 (C2) sustains the high proliferative potential of glioma cells. The upregulation of oCGIs and enhancers related genes in C2 results in glioma patients exhibiting resistance to radiotherapy and chemotherapy. These findings were further validated through glioma cell line related experiments. Our study offers insight into the pathogenesis of glioma and provides a strategy to treat this challenging disease.