iScience · 2019 · 64 citations · 61 references
Life SciencesGeneticsMolecular BiologyGene ExpressionGene RegulationTranscriptional RegulationCellular Responses To HypoxiaCircadian Clock MechanismsCircadian Gene ExpressionCircadian Molecular MechanismsCircadian PhysiologyHypoxia AdaptationCellular Hypoxia SignalingHif-1 Alpha RegulationHypoxiaHypoxia-inducible Factor RegulationHypoxia-inducible Factor SignalingNegative Clock RegulatorsProtein Half-lifeShort Hairpin Rna
The circadian clock and the hypoxia-signaling pathway are regulated by an integrated interplay of positive and negative feedback limbs that incorporate energy homeostasis and carcinogenesis. We show that the negative circadian regulator CRY1 is also a negative regulator of hypoxia-inducible factor (HIF). Mechanistically, CRY1 interacts with the basic-helix-loop-helix domain of HIF-1α via its tail region. Subsequently, CRY1 reduces HIF-1α half-life and binding of HIFs to target gene promoters. This appeared to be CRY1 specific because genetic disruption of CRY1, but not CRY2, affected the hypoxia response. Furthermore, CRY1 deficiency could induce cellular HIF levels, proliferation, and migration, which could be reversed by CRISPR/Cas9- or short hairpin RNA-mediated HIF knockout. Altogether, our study provides a mechanistic explanation for genetic association studies linking a disruption of the circadian clock with hypoxia-associated processes such as carcinogenesis.
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Transcriptional Architecture and Chromatin Landscape of the Core Circadian Clock in Mammals
Nobuya Koike, Seung Hee Yoo, Hung-Chung Huang et al. · Science · 2012 · 1.5K citations · Full text