title: A HIF-independent mediator of transcriptional responses to oxygen deprivation in Caenorhabditis elegans.
abstract: The adaptive response to hypoxia is accompanied by widespread transcriptional changes that allow for prolonged survival in low oxygen. Many of these changes are directly regulated by the conserved hypoxia-inducible factor-1 (HIF-1) complex; however, even in its absence, many oxygen-sensitive transcripts in Caenorhabditis elegans are appropriately regulated in hypoxia. To identify mediators of these non-HIF-dependent responses, we established a hif-1 mutant reporter line that expresses GFP in hypoxia or when worms are treated with the hypoxia mimetic cobalt chloride (CoCl2). The reporter is selective and HIF independent, in that it remains insensitive to a number of cellular stresses, but is unaffected by mutation of the prolyl hydroxylase egl-9, suggesting that the regulators of this response pathway are different from those controlling the HIF pathway. We used the HIF-independent reporter to screen a transcription factor RNA interference (RNAi) library and identified genes that are required for hypoxia-sensitive and CoCl2-induced GFP expression. We identified the zinc finger protein BLMP-1 as a mediator of the HIF-independent response. We show that mutation of blmp-1 renders animals sensitive to hypoxic exposure and that blmp-1 is required for appropriate hypoxic-induced expression of HIF-independent transcripts. Further, we demonstrate that BLMP-1 is necessary for an increase of hypoxia-dependent histone acetylation within the promoter of a non-HIF-dependent hypoxia response gene.
authors.affiliation: Department of Biochemistry and Molecular Biology, Virginia Commonwealth University School of Medicine, Richmond, Virginia 23298 Massey Cancer Center, Virginia Commonwealth University School of Medicine, Richmond, Virginia 23298.
authors.forename: Divya
authors.initials: D
authors.lastname: Padmanabha
authors.affiliation: Department of Biological Sciences, University of North Texas, Denton, Texas 76203.
authors.forename: Pamela A
authors.initials: PA
authors.lastname: Padilla
authors.affiliation: Department of Biochemistry and Molecular Biology, Virginia Commonwealth University School of Medicine, Richmond, Virginia 23298.
authors.forename: Young-Jai
authors.initials: YJ
authors.lastname: You
authors.affiliation: Department of Biochemistry and Molecular Biology, Virginia Commonwealth University School of Medicine, Richmond, Virginia 23298 Massey Cancer Center, Virginia Commonwealth University School of Medicine, Richmond, Virginia 23298 kdbaker@vcu.edu.
authors.forename: Keith D
authors.identifier: http://orcid.org/0000-0002-6755-1697
authors.initials: KD
authors.lastname: Baker
mesh_terms: D000818:Animals; D017173:Caenorhabditis elegans / Q000235:genetics* / Q000378:metabolism; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000502:physiology*; D015687:Cell Hypoxia; D005786:Gene Expression Regulation; D009154:Mutation; D012097:Repressor Proteins; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*; D014158:Transcription, Genetic
chemical_list: D029742:Caenorhabditis elegans Proteins; C541178:HIF-1 protein, C elegans; D012097:Repressor Proteins; D014157:Transcription Factors; C000600050:blmp-1 protein, C elegans
keywords: BLMP-1; C. elegans; HIF independent; hypoxia