EZH2 overexpression establishes a unique and conserved super-enhancer–associated transcriptional landscape. EZH2 overexpression establishes a unique and.

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EZH2 overexpression establishes a unique and conserved super-enhancer–associated transcriptional landscape. EZH2 overexpression establishes a unique and conserved super-enhancer–associated transcriptional landscape. A, box plot of RNA-seq expression in units of FPKM of murine genes associated with SEs that are gained (1,812 genes), unchanged (4,421 genes), or lost (432 genes) in tumor versus WT lung tissues. Significance was calculated using a two-tailed t test. **, P < 2e−4; ***, P < 2e−6. B, scatter plot of normalized enrichment score (NES) versus false discovery rate (FDR) q-value comparing MSigDB curated gene set enrichment in murine tumor versus WT SE-associated genes. The x-axis shows NES for evaluated gene sets. The y-axis shows false FDR q-value for each gene set. Gene sets upregulated in tumors have a high positive NES, whereas downregulated gene sets have a negative NES. Dotted line indicates significance cutoff q-value of 0.05. Red dots indicate PRC2-associated signatures, n = 8. C, SE-associated gene set enrichment analysis showing downregulation of EED targets in murine tumor versus WT tissues from RNA-seq analysis. D, heat map of LFC in H3K27ac over H3K27me3 signals at SE-containing regions. Blue regions indicate SEs with strong gains of H3K27me3 in tumor versus WT, whereas red regions indicate those with strong losses. E, dot plot of RNA-seq expression in units of log10 FPKM for genes proximal to SE regions with a strong gain of H3K27me3 in murine tumor versus WT. Significance was calculated with a two-tailed t test. **, P < 1e−5. F, 32 mouse genes proximal to SE regions with strong H3K27me3 gain in EZH2-overexpressing tumors. G, gene tracks of ChIP-seq signals in units of rpm/bp for H3K27ac and H3K27me3 at the DUSP4 locus in either murine WT or tumor lung tissues. H, Western blot analysis of lysates prepared from murine normal lung (N-1, N-2, and N-3) and lung tumor (T-1, T-2, and T-3) samples. I, box plot of ssGSEA comparing the enrichment of our mouse H3K27me3 gene set in human TCGA lung adenocarcinomas with high EZH2 levels and normal lung tissue. The H3K27me3 gene set is comprised of the 32 mouse genes proximal to SE regions with strong H3K27me3 gain in murine EZH2-overexpressing tumors. Haikuo Zhang et al. Cancer Discov 2016;6:1006-1021 ©2016 by American Association for Cancer Research