Hypoxia-inducible Factor-1 (HIF-1)-independent Hypoxia Response of the Small Heat Shock Protein hsp-16.1 Gene Regulated by Chromatin-remodeling Factors in the Nematode Caenorhabditis elegans

Oxygen deprivation is accompanied by the coordinated expression of numerous hypoxia-responsive genes, many of which are controlled by hypoxia-inducible factor-1 (HIF-1). However, the cellular response to hypoxia is not likely to be mediated by HIF-1 alone, and little is known about HIF-1-independent hypoxia responses. To better establish the molecular mechanisms of HIF-1-independent hypoxia responses, we sought to characterize the molecular basis of the hypoxia response of the hsp-16.1 gene in the nematode Caenorhabditis elegans; this gene has been shown to be induced by hypoxia independently of hif-1. Using affinity purification followed by LC-MS/MS, we identified HMG-1.2 as a protein that binds to a specific promoter region under hypoxic conditions. By systematic prediction followed by validation of these interactions through RNAi, we identified the chromatin modifiers isw-1 and hda-1, histone H4, and NURF-1 chromatin-remodeling factors as new components of the hif-1-independent hypoxia response. These data suggest that the modulation of nucleosome positioning at the hsp-16.1 promoter may be important for the hypoxia response. In addition, we found that calcineurin acts independently of hif-1 to modulate the cellular response to hypoxia and that calcium ions are necessary for the induction of hsp-16.1 under hypoxic conditions.