Systematic analysis of DNA methylation-mediated TF dysregulation on lncRNAs reveals critical roles in tumor immunity

Emerging evidence suggests that DNA methylation affects transcriptional regulation and expression perturbations of long non-coding RNAs (lncRNAs) in cancer. However, a comprehensive investigation into the transcriptional control of DNA methylation-mediated dysregulation of transcription factors (TFs) on lncRNAs has been lacking. Here, we integrated the transcriptome, methylome, and regulatome across 21 hu-man cancers and systematically identified the transcriptional regulation of DNA methylation-mediated TF dysregulations (DMTDs) on lncRNAs. Our findings reveal that TF regulation of lncRNAs is significantly impacted by DNA methylation. Comparative analysis of DMTDs on mRNAs revealed a conserved pattern of TFs involvement. Pan-cancer Methylation TFs (MethTFs) and Methylation LncRNAs (MethLncRNAs) were identified, and were found to be closely associated with cancer hallmarks and clinical features. In-depth analysis of co-expressed mRNAs with pan-cancer MethLncRNAs unveiled frequent disruptions in cancer immunity, particularly in the context of inflammatory response. Furthermore, we identified five immune-related network modules that contribute to im-mune cell infiltration in cancer. Immune-related subtypes were subsequently classified, characterized by high levels of im-mune cell infiltration, expression of immunomodulatory genes, and relevant immune cytolytic activity score, major his-tocompatibility complex score, response to chemotherapy, and prognosis. Our findings provide valuable insights into cancer immunity from the epigenetic and transcriptional regulation perspective.

Automated summary

This study comprehensively investigated the transcriptional control of DNA methylation-mediated dysregulation of transcription factors (TFs) on long non-coding RNAs (lncRNAs) in cancer. The findings revealed that TF regulation of lncRNAs is significantly impacted by DNA methylation. The study also identified DNA methylation-associated TFs and lncRNAs that are closely associated with cancer hallmarks and clinical features. The research provided valuable insights into cancer immunity from the epigenetic and transcriptional regulation perspective.