As an epigenetic co-activator for gene transcription, our data reveal that loss of Mll4 abrogates enhancers to downregulate Dnmt3a and Dnmt1 expression in murine tumor cells, suggesting the increased ERVs transcripts we noted in Mll4−/− melanoma cells may indirectly result from the defects in DNA methylation-mediated epigenetic silencing. Here, KMT2D is linked to melanoma.