Schematic representation of transcriptional gene repression by enhancer of zeste homolog 2 (EZH2). (A) In a mesenchymal stem cell or in a soft tissue sarcoma (STS) cell, EZH2 interacts with suppressor of zeste 12 (SUZ12) and embryonic ectoderm development (EED), the other core components of the Polycomb repressor complex 2 (PRC2) complex that is involved in the initiation of gene repression. By the methyltransferase activity of EZH2, histone H3 is methylated on K27 thus generating the epigenetic mark H3K27Me3 that serves as a signal for the recruitment of PRC1 complex. PRC1 DNA binding prevents the access of antagonistic chromatin remodeling factors, such as the SWI/SNF complex, thus stabilizing the repressive state of the chromatin. The PRC2-associated activity of histone deacetylase (HDAC) and the interaction of EZH2 with DNA methyltransferases (DMNTs) allow a further compaction of chromatin by means of histone deacetylation and DNA methylation, respectively (synergism of epigenetic mechanisms). (B) During differentiation the level of EZH2 decreases with consequent reduction of PRC2 complex. H3K27 becomes hypomethylated and the SWI/SNF complex facilitates the DNA binding of tissue specific transcription factors (TF) that engage histone acetyltransferase (HAT) to allow initiation of transcription.