Genes up-regulated by short-term hypoxia in N2.

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 to identify HIF-1 downstream genes and 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) Are any of these hif-1-dependent genes essential to survival in hypoxia? (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 and stress response. Some HIF-1-dependent hypoxia-responsive genes like efk-1 and phy-2 dramatically impact survival in hypoxic conditions. Genes regulated by HIF-1 and hypoxia overlap with genes responsive to hydrogen sulfide, also overlap with genes regulated by DAF-16. The genomic regions that co-immunoprecipitate with HIF-1 are strongly enriched for genes involved in stress response. 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.

氧气对于所有需氧生物（aerobic organisms）均为必需物质。在正常发育、疾病发生及稳态维持过程中，生物往往会受到低氧（hypoxia，氧剥夺）的胁迫。低氧诱导转录因子（hypoxia-inducible transcription factors, HIFs）是低氧应答的核心调控因子，在后生动物（metazoans）中进化保守。模式生物秀丽隐杆线虫（C. elegans）中的HIF同源蛋白为HIF-1。本研究旨在解析短期低氧应答机制，以鉴定秀丽隐杆线虫中HIF-1的下游基因，并明确其直接靶标。核心研究问题包括：(1) 哪些基因在短期低氧胁迫下呈现差异表达？(2) 上述基因表达变化中，哪些依赖于HIF-1的功能？(3) 这些依赖HIF-1的基因中，是否存在对低氧环境下生存至关重要的基因？(4) 哪些基因是HIF-1的直接靶标？我们整合全基因组基因表达分析与染色质免疫共沉淀测序（chromatin immunoprecipitation sequencing, ChIP-seq）实验来解答上述科学问题。与其他已发表研究结果一致，本研究发现HIF-1依赖型低氧应答基因参与代谢与应激响应过程。部分HIF-1依赖型低氧应答基因（如efk-1与phy-2）对低氧条件下的生物生存具有显著影响。受HIF-1与低氧共同调控的基因，既与硫化氢（hydrogen sulfide）应答基因存在重叠，也与DAF-16调控的基因存在交集。与HIF-1共免疫沉淀的基因组区域，显著富集于应激响应相关基因。进一步研究表明，部分潜在HIF-1直接靶标在短期低氧条件下存在差异表达，或可被增强HIF-1活性的突变所调控。