Transcriptome analyses describe the consequences of persistent HIF-1 over-activation inCaenorhabditis elegans

Abstract

Metazoan animals rely on oxygen for survival, but during normal development and homeostasis, animals are often challenged by hypoxia (low oxygen). In metazoans, many of the critical hypoxia responses are mediated by the evolutionarily conserved hypoxia-inducible transcription factors (HIFs). The stability and activity of HIF complexes are strictly regulated. In the model organismC. elegans, HIF-1 stability and activity are negatively regulated by VHL-1, EGL-9, RHY-1 and SWAN-1. Importantly,C. elegansmutants carrying strong loss-of-function mutations in these genes are viable, and this provides opportunities to interrogate the molecular consequences of persistent HIF-1 over-activation. We find that the genome-wide gene expression patterns are compellingly similar in these mutants, supporting models in which RHY-1, SWAN-1 and EGL-9 function in common pathway(s) to regulate HIF-1 activity. These studies illuminate the diversified biological roles played by HIF-1, including metabolism, hypoxia and other stress responses, reproduction and development. Genes regulated by persistent HIF-1 over-activation overlap with genes responsive to pathogens, and they overlap with genes regulated by DAF-16. As crucial stress regulators, HIF-1 and DAF-16 converge on key stress-responsive genes and function synergistically to enable hypoxia survival.

Whole genome profiling of short-term hypoxia induced genes and identification of HIF-1 binding sites provide insights into HIF-1 function in Caenorhabditis elegans

“…We anticipated that some of the genes that were responsive to short-term hypoxia would also be differentially expressed in mutants that over-expressed HIF-1 targets. To explore this question further, we compared the findings summarized in S6 and S7 Tables (genes positively or negatively regulated by HIF-1 in 2-hour hypoxia treatments) with genes that were mis-regulated in the four HIF-1 negative regulator mutants [ vhl-1(ok161) , rhy-1(ok1402) , egl-9(sa307) , and swan-1(ok267);vhl-1(ok161) double mutants; See the related study [ 26 ] and S1 Table ]. We identified 23 genes were positively regulated by HIF-1 under short-term hypoxia and up-regulated in all the four HIF-1 negative regulator mutants ( Table 3 ).…”

“…This manuscript describes gene expression changes in N2 wild type animals and hif-1(ia04) mutants under hypoxia and nomoxia. Genes expression changes in vhl-1(ok161) , egl-9(sa307) , rhy-1(ok1402) and swan-1(ok267);vhl-1(ok161) double mutants have been described in a related study [ 26 ]. The microarray raw and probeset summary data had been deposited to NCBI’s Gene Expression Omnibus, the accession number is GSE228851.…”