Clioquinol as an inhibitor of JmjC-histone demethylase exhibits common and unique histone methylome and transcriptome between clioquinol and hypoxia

Authors
Moon, YunwonChae, SehyunYim, SujinYang, Eun GyeongChoe, JungwooHyun, JiyeonChang, RakwooHwang, DaeheePark, Hyunsung
Issue Date
2022-07
Publisher
CELL PRESS
Citation
iScience, v.25, no.7
Abstract
Clioquinol (CQ) is a hypoxic mimicker to activate hypoxia-inducible factor-1 alpha (HIF-1 alpha) by inhibiting HIF-1 alpha 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-alpha activator, and an alternative therapeutic agent in hypoxia-based diseases.
Keywords
GENE-EXPRESSION; ALZHEIMERS-DISEASE; BINDING; INTEGRATION; UBIQUITINATION; CHELATOR; PHASE-2; FAMILY; JHDM2A
URI
https://pubs.kist.re.kr/handle/201004/114894
DOI
10.1016/j.isci.2022.104517
Appears in Collections:
KIST Article > 2022
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