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Mass coral bleaching and mortality have recently occurred where reefs have experienced chronic low oxygen events. However, the mechanistic basis of tolerance to oxygen levels inadequate to sustain normal functioning (i.e. hypoxia) and whether it contributes to bleaching susceptibility, remain unknown. We therefore experimentally exposed colonies of the environmentally resilient <jats:italic>Acropora tenuis<\/jats:italic>, a common reef\u2010building coral from the Great Barrier Reef, to deoxygenation\u2013reoxygenation stress that was aligned to their natural night\u2013day light cycle. Specifically, the treatment involved removing the \u2018night\u2010time O<jats:sub>2<\/jats:sub> buffer\u2019 to challenge the inherent hypoxia thresholds. RNA\u2010Seq analysis revealed that coral possess a complete and active hypoxia\u2010inducible factor (HIF)\u2010mediated hypoxia response system (HRS) homologous to other metazoans. As expected, <jats:italic>A. tenuis<\/jats:italic> exhibited bleaching resistance and showed a strong inducibility of HIF target genes in response to deoxygenation stress. We applied this same approach in parallel to a colony of <jats:italic>Acropora selago<\/jats:italic>, known to be environmnetally susceptible, which conversely exhibited a bleaching phenotype response. This phenotypic divergence of <jats:italic>A. selago<\/jats:italic> was accompanied by contrasting gene expression profiles indicative of varied effectiveness of their HIF\u2010HRS. Based on our RNA\u2010Seq analysis, we propose (a) that the HIF\u2010HRS is central for corals to manage deoxygenation stress and (b) that key genes of this system (and the wider gene network) may contribute to variation in coral bleaching susceptibility. Our analysis suggests that heat shock protein (hsp) 70 and 90 are important for low oxygen stress tolerance and further highlights how hsp90 expression might also affect the inducibility of coral HIF\u2010HRS in overcoming a metabolic crisis under deoxygenation stress. We propose that differences in coral HIF\u2010HRS could be central in regulating sensitivity to other climate change stressors\u2014notably thermal stress\u2014that commonly drive bleaching.<\/jats:p>","DOI":"10.1111\/gcb.15436","type":"journal-article","created":{"date-parts":[[2020,11,16]],"date-time":"2020-11-16T21:59:06Z","timestamp":1605563946000},"page":"312-326","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":77,"title":["Divergent expression of hypoxia response systems under deoxygenation in reef\u2010forming corals aligns with bleaching susceptibility"],"prefix":"10.1111","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4234-7673","authenticated-orcid":false,"given":"Rachel","family":"Alderdice","sequence":"first","affiliation":[{"name":"Climate Change Cluster Faculty of Science University of Technology Sydney Ultimo NSW Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5326-2520","authenticated-orcid":false,"given":"David J.","family":"Suggett","sequence":"additional","affiliation":[{"name":"Climate Change Cluster Faculty of Science University of Technology Sydney Ultimo NSW Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4080-9010","authenticated-orcid":false,"given":"Anny","family":"C\u00e1rdenas","sequence":"additional","affiliation":[{"name":"Department of Biology University of Konstanz Konstanz Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3778-7460","authenticated-orcid":false,"given":"David J.","family":"Hughes","sequence":"additional","affiliation":[{"name":"Climate Change Cluster Faculty of Science University of Technology Sydney Ultimo NSW Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1792-4790","authenticated-orcid":false,"given":"Michael","family":"K\u00fchl","sequence":"additional","affiliation":[{"name":"Climate Change Cluster Faculty of Science University of Technology Sydney Ultimo NSW Australia"},{"name":"Marine Biology Section Department of Biology University of Copenhagen Helsing\u00f8r Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3431-2104","authenticated-orcid":false,"given":"Mathieu","family":"Pernice","sequence":"additional","affiliation":[{"name":"Climate Change Cluster Faculty of Science University of Technology Sydney Ultimo NSW Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4555-3795","authenticated-orcid":false,"given":"Christian R.","family":"Voolstra","sequence":"additional","affiliation":[{"name":"Department of Biology University of Konstanz Konstanz Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2020,11,16]]},"reference":[{"issue":"1","key":"e_1_2_9_2_1","article-title":"Defining the tipping point. 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