Systematic multivariate analysis of chromatin complex dependencies reveals Set1C/COMPASS as a melanoma-enriched epigenetic vulnerability

Melanoma exhibits lineage-specific transcriptional programs that may create selective epigenetic vulnerabilities. To identify melanoma-enriched chromatin dependencies, we analyzed large-scale CRISPR gene-dependency data from cancer cell lines together with curated epigenetic complex annotations. This analysis identified the H3K4 methyltransferase complex Set1C/COMPASS as a melanoma-enriched dependency, with CXXC1 emerging as a selectively required subunit in a subset of melanoma cell lines. Functional validation using iterative indirect immunofluorescence imaging (4i) and quantitative single-cell analysis showed that siRNA-mediated depletion of CXXC1 reduced global H3K4me3 levels and impaired proliferation in CXXC1-dependent melanoma cell lines. To define the transcriptional consequences of Set1C/COMPASS perturbation, we performed bulk RNA sequencing (RNA-seq) following siRNA-mediated depletion of CXXC1. Four melanoma cell lines (UACC62, LOXIMVI, MALME3M, and SKMEL28) were transfected with siCXXC1 or a non-targeting control (siNTC), with three independent biological replicates per condition. RNA was harvested 96 hours post-transfection and sequenced to quantify genome-wide expression changes associated with CXXC1 depletion. Transcriptomic analysis revealed suppression of proliferation-associated gene expression programs, including MYC and E2F target signatures, in CXXC1-dependent melanoma cell lines.