HIF-INDEPENDENT RESPONSES IN HYPOXIA
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, I established a hif-1 mutant reporter line that expresses GFP in hypoxia or when worms are treated with the hypoxia mimetic cobalt chloride (cobalt chloride). 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. I used the HIF-independent reporter to screen a transcription factor RNAi library and identified genes that are required for hypoxia sensitive and cobalt chloride-induced GFP expression. Three mediators of the HIF-independent response zinc finger protein BLMP-1, chromatin remodeling factor LIN-40, and T-box transcription factor TBX-38 were isolated as mediators of the HIF-independent response. First, we show that mutation of blmp-1 renders animals sensitive to hypoxic exposure and that blmp-1 it 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. Additionally, we explore BLMP-1’s role in two hypoxia-regulated physiological processes namely unfolded protein response and collagen formation. We also briefly investigate the role of LIN-40 in the hypoxia response.