Work

An m5C-associated NSUN5–YBX1–CENPF programme marks melanoma cell states and immune features

Year: 2026

Type: article

Abstract: Background: C)-associated programmes may help characterise melanoma cell states and their immune context. We investigated an NSUN5-YBX1-CENPF (NYC) programme using patient-matched sequencing, experimental perturbation and multiscale transcriptomic analyses. Methods: C-MeRIP-seq and matched Input RNA data from three melanoma-adjacent-normal patient pairs, using a paired edgeR interaction model for regional IP enrichment. Tissue and cell experiments included NSUN5 knockdown, CENPF-targeted MeRIP-qPCR and western blotting. Clinical analyses considered proliferation and sampling site. Trajectory and regulatory inference were restricted to malignant cells from GSE215120, with patient-level summaries. Treatment-associated changes were examined in 43 paired patients from GSE91061. Computational perturbation and transcriptomic signature reversal prioritised candidate regulators and compounds. Results: C enrichment and protein abundance. NYC was associated with proliferation; its survival association did not persist after proliferation adjustment. Within malignant cells, NYC-High retained an association with an immune-resistance expression programme after G2M/E2F and depth adjustment (nine patients; BH q = 0.0156). Regulatory analyses prioritised MLX, whose simulated knockout and overexpression produced opposing reference-flow alignments (BH q = 0.0134 and 0.0201). MLX regulon activity was associated with glycolysis and oxidative phosphorylation after adjustment. In GSE91061, responders showed a greater treatment-associated NYC decrease than non-responders (mean change difference -0.209; permutation P = 0.0138). Drug screening generated candidates for experimental testing. Conclusions: C-associated framework connecting patient-derived molecular observations to malignant-cell states and immune features. YBX1 remains a candidate reader, and regulatory, treatment-associated and drug-prioritisation findings do not establish a complete causal pathway or a clinically validated predictive biomarker.

Source: Frontiers in Immunology

DOI: 10.3389/fimmu.2026.1952519