Epigenetic regulation is a dynamic and reversible process that controls gene expression. Abnormal function results in downregulation or upregulation of pathways leading to diseases, such as cancer. The enzymes that establish and maintain epigenetic marks, such as histone methyltransferases (HMTs), are therapeutic targets as their and, importantly, the epigenetic modifications are reversible. Noteworthy, HMTs, as the other epigenetic enzymes and readers, form together multiprotein complexes that in concert regulate histone marks. To probe the epigenetic protein complexes in a biological system, we developed a reliable chemical biology high-content imaging strategy to screen compound libraries on multiple histone marks inside cells simultaneously. The advantage is double: (1) it identifies directly a drug that is active in cells on a specific histone mark and (2) it reveals the crosstalk between the epigenetic marks. By this approach, we identified that compound 4, a published CARM1 (PRMT4) inhibitor, inhibits both histone mark H3R2me2a (regulated by CARM1) and H3K79me2 (regulated by DOT1L) pointing out a synergistic interaction between the two HMTs. The results obtained by the screening assay were validated by mass spectrometry and other techniques confirming the crosstalk between the two marks and HMTs. Prompted by the interaction between CARM1 and DOT1L we combined compound 4 and DOT1L inhibitor EPZ-5676 resulting in a stronger cell proliferation inhibition and apoptosis, indicating that our approach provides also a novel strategy to identify effective synergistic drug combinations for cancer therapy.