Dysregulated expression or mutation of H3K9me3/H4K20me3 histone methyltransferases (HMTases) in cancer cells may lead to perturbed sequential deposition of H3K9me3 and H4K20me3, or altered patterns of H3K9me3 and H4K20me3 deposition, thus leading to heterochromatin dysregulation and genome instability. This evidence concerns the gene PRDM9 and cancer.