Oxygen is the final electron acceptor in the reactions by which cells metabolize macromolecules to generate energy for cellular functions. When oxygen becomes limiting (a condition called hypoxia), then organisms must adapt to survive. The hypoxia-inducible factor (HIF) transcription complexes are evolutionarily conserved regulators of hypoxia response. In C. elegans, the HIF alpha and beta subunits are encoded by the
hif-1 and
aha-1 genes. While wild-type C. elegans can survive and reproduce in 1% oxygen, mutants lacking
hif-1 function cannot. In the past few years, studies from many groups have shown that
hif-1 has roles in aging, stress response, neuronal development and function, and pathogen resistance. The conserved EGL-9/VHL-1 pathway regulates oxygen-dependent degradation of HIF-1 protein. Through forward genetic screens, we have discovered that
egl-9,
rhy-1 and
swan-1 repress HIF-1 transcriptional activity via
vhl-1-independent pathways. The molecular mechanisms by which these genes function to limit HIF-1 activity are largely unknown. To better understand and compare impacts that loss-of-function mutations in these genes have on HIF-1-mediated transcription, we employed microarray analyses. The results of these studies identify ninety-seven genes that are up-regulated in
vhl-1(
ok161),
rhy-1(
ok1402),
egl-9(
sa307), and
swan-1 (
ok267);
vhl-1 (
ok161) mutants, relative to wild-type. Additionally, these analyses further distinguish the effects of short-term hypoxia treatment from the effects of persistent activation of HIF-1 in
egl-9 or
vhl-1 mutants. Experiments are ongoing to examine the roles of individual genes in the HIF-1 pathway on stress response, aging, and pathogen resistance.