Examine the epigenetic consequences of KMT2D loss in melanoma using ChIP-seq profiling [CUT&Run]

Cellular plasticity contributes to melanoma progression and resistance to treatment, but the epigenetic mechanisms driving these changes are not well understood. In a Braf-mutant mouse model, we show that loss of Kmt2d, an enzyme that adds H3K4me1 to enhancers, speeds up melanoma development and shifts cells toward a neural crest-like state. Using single-cell multiome analysis, we found that this shift is driven by increased activity of TFAP2 transcription factors, linked to changes at enhancer regions. Kmt2d loss also leads to a more immunosuppressive tumor environment, with higher levels of suppressive immune cells. This study provides the first genetic evidence that enhancer disruption plays a key role in cell identity changes in melanoma.