Importantly, loci most impacted by both DNA hypermethylation (in EED or WDR5 depletions) and hypomethylation (in CBX4 and RNF2 depletions) overlapped extensively among the knockdowns indicating multi-layered epigenetic co-regulation, and these loci were strongly susceptible to aberrant hypermethylation in cancer. The gene discussed is CBX4; the disease is cancer.