Regulation of the IRE1α branch of the UPR by EZH2 in GCB DLBCL. Within GCB DLBCL, the histone methyltransferase EZH2 trimethylates the tail of histone H3 at lysine 27 (H3K27m3), which represses the expression of IRE1α. The use of an EZH2 inhibitor (EZH2i) relieves the repression of IRE1α, which with ER stress converts XBP1 to its active, spliced form (XBP1s). XBP1s then initiates a transcriptional program, which in the GCB DLBCL context, antagonizes lymphomagenesis. ERAD, ER-associated degradation; P, phosphorylation. Professional illustration by Patrick Lane, ScEYEnce Studios.