EZH2 inhibition results in genome-wide PRC2 redistribution

Summary Histone methyltransferase polycomb repressive complex 2 (PRC2) plays a critical role in cell fate determination, and its catalytic subunit EZH2 is a key oncogenic driver in GCB-DLBCL. EZH2 inhibition in some GCB-DLBCL cell models leads to a global loss of H3K27me3, the derepression of a subset of silenced PRC2 target genes, and ultimately cell death. Here we show that EZH2 inhibition causes global redistribution of PRC2 components. We observe a reduction in the already-low levels of PRC2 at active genes. On the other hand, focal PRC2 accumulation and concomitant H3K27me3 retention occur at many canonical embryonic stem cell PRC2 nucleation sites. PRC2 accumulation is also enriched in plasma/memory cell genes repressed by PRC2 activity in the germinal center. We see PRC2 redistribution to, and H3K27me3 retention at, differentiation-related genes not only in cell lines that are insensitive to killing by EZH2 inhibition, but also in sensitive cell lines. Thus, PRC2 redistribution to B cell differentiation genes is not sufficient to explain the resistance to EZH2 inhibitors in some DLBCL cell lines.