标题：Clioquinol as an inhibitor of JmjC-histone demethylase exhibits common and unique histone methylome and transcriptome between clioquinol and hypoxia
摘要：SummaryClioquinol (CQ) is a hypoxic mimicker to activate hypoxia-inducible factor-1α (HIF-1α) by inhibiting HIF-1α specific asparaginyl hypoxylase (FIH-1). The structural similarity of the Jumonji C (JmjC) domain between FIH-1 and JmjC domain-containing histone lysine demethylases (JmjC-KDMs) led us to investigate whether CQ could inhibit the catalytic activities of JmjC-KDMs. Herein, we showed that CQ inhibits KDM4A/C, KDM5A/B, and KDM6B and affects H3K4me3, H3K9me3, and H3K27me3 marks, respectively. An integrative analysis of the histone methylome and transcriptome data revealed that CQ-mediated JmjC-KDM inhibition altered the transcription of target genes through differential combinations of KDMs and transcription factors. Notably, functional enrichment of target genes showed that CQ and hypoxia commonly affected the response to hypoxia, VEGF signaling, and glycolysis, whereas CQ uniquely altered apoptosis/autophagy and cytoskeleton/extracellular matrix organization. Our results suggest that CQ can be used as a JmjC-KDM inhibitor, HIF-α activator, and an alternative therapeutic agent in hypoxia-based diseases.Graphical abstractDisplay OmittedHighlights•Both hypoxia and clioquinol (CQ) inhibit histone lysine demethylases (KDMs)•CQ affects H3K4me3, H3K9me3, and H3K27me3 marks upon inhibition•CQ treatment-induced histone methylome changes affect target gene transcription•Histone methylome predicts TFs underlying transcription of CQ target genesBiochemistry; Molecular biology; Transcriptomics
