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During pulmonary infection, host alveolar macrophages compartmentalize Cu into the phagosome and <jats:italic>C. neoformans<\/jats:italic> Cu\u2010detoxifying metallothioneins, MT1 and MT2, are required for survival of the pathogen. In contrast, during brain colonization the <jats:italic>C. neoformans<\/jats:italic> Cu<jats:sup>+<\/jats:sup> importers Ctr1 and Ctr4 are required for virulence. Central for the regulation and expression of both the Cu detoxifying MT1\/2 and the Cu acquisition Ctr1\/4 proteins is the Cu\u2010metalloregulatory transcription factor Cuf1, an established <jats:italic>C. neoformans<\/jats:italic> virulence factor. Due to the importance of the distinct <jats:italic>C. neoformans<\/jats:italic> Cu homeostasis mechanisms during host colonization and virulence, and to the central role of Cuf1 in regulating Cu homeostasis, we performed a combination of RNA\u2010Seq and ChIP\u2010Seq experiments to identify differentially transcribed genes between conditions of high and low Cu. We demonstrate that the transcriptional regulation exerted by Cuf1 is intrinsically complex and that Cuf1 also functions as a transcriptional repressor. The Cu\u2010 and Cuf1\u2010dependent regulon in <jats:italic>C. neoformans<\/jats:italic> reveals new adaptive mechanisms for Cu homeostasis in this pathogenic fungus and identifies potential new pathogen\u2010specific targets for therapeutic intervention in fungal infections.<\/jats:p>","DOI":"10.1111\/mmi.13960","type":"journal-article","created":{"date-parts":[[2018,4,2]],"date-time":"2018-04-02T17:52:51Z","timestamp":1522691571000},"page":"473-494","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":43,"title":["Genome\u2010wide analysis of the regulation of Cu metabolism in <i>Cryptococcus neoformans<\/i>"],"prefix":"10.1111","volume":"108","author":[{"given":"Sarela","family":"Garcia\u2010Santamarina","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Cancer Biology Duke University School of Medicine Durham NC USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard 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