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

Abstract

Oxygen is essential to all the aerobic organisms. However, during normal development, disease and homeostasis, organisms are often challenged by hypoxia (oxygen deprivation). Hypoxia-inducible transcription factors (HIFs) are master regulators of hypoxia response and are evolutionarily conserved in metazoans. The homolog of HIF in the genetic model organism C. elegans is HIF-1. In this study, we aimed to understand short-term hypoxia response and to identify HIF-1 direct targets in C. elegans. The central research questions were: (1) which genes are differentially expressed in response to short-term hypoxia? (2) Which of these changes in gene expression are dependent upon HIF-1 function? (3) How do HIF-1-dependent hypoxia-responsive genes affect hypoxia adaptation? (4) Which genes are the direct targets of HIF-1? We combine whole genome gene expression analyses and chromatin immunoprecipitation sequencing (ChIP-seq) experiments to address these questions. In agreement with other published studies, we report that HIF-1-dependent hypoxia-responsive genes are involved in metabolism, oxidation-reduction process, and stress response. Some HIF-1-dependent hypoxia-responsive genes like efk-1 and phy-2 dramatically impact survival in hypoxic conditions. HIF-1 co-immunoprecipitates with genomic regions proximal genes involved in stress response, protein processing in endoplasmic reticulum, and cell recognition. Further, some of these potential HIF-1 direct targets are differentially expressed under short-term hypoxia or are differentially regulated by mutations that enhance HIF-1 activity.