Cooperativity of Stress-Responsive Transcription Factors in Core Hypoxia-Inducible Factor Binding Regions
Figure 5
Transcriptional targets of stress-responsive transcription factors are enriched among core hypoxia-responsive genes.
(A) Gene-set enrichment analysis on a set of 11673 genes sorted by their response to hypoxia according to a meta-analysis of hypoxia gene expression experiments (ref. 13). The graph depicts the normalized enrichment score of 3174 gene sets from the curated collection (C2) of the GSEA molecular signatures database v3.0, that includes sets of transcription factor target genes. Solid circles highlight gene-sets derived from studies on HIF1 (black, ELVIDGE_HYPOXIA_UP and SEMENZA_HIF1_TARGETS), CEBPA/B (purple, GERY_CEBP_TARGETS, HALMOS_CEBPA_TARGETS_UP and TAVOR_CEBPA_TARGETS_UP), CREB1/ATF5 (orange, GHO_ATF5_TARGETS_DN and MCCLUNG_CREB1_TARGETS_UP) and AP1 (green, OZANNE_AP1_TARGETS_UP) transcriptional targets. The vertical blue line corresponds to an FDR-adjusted p-value of 0.05. (B) GSEA analysis of hypoxia-responsive genes (see A) against the GERY_CEBPA_TARGETS (M12338, derived from the GEO dataset GSE2188) gene-set. Hypoxic response is rank-ordered in the horizontal axis (Rank in ordered dataset). Black bars indicate the position of individual targets in the CEBPA gene-set. The graph on top (green curve) represents enrichment scores of CEBPA targets across hypoxia responsive genes, indicating positive correlation between the two. The gradient color bar indicates positive (red) and negative (blue) correlation boundaries.