Hypoxia-induced gene expression results from selective mRNA partitioning to the endoplasmic reticulum

Nucleic Acids Res. 2015 Mar 31;43(6):3219-36. doi: 10.1093/nar/gkv167. Epub 2015 Mar 8.


Protein synthesis is a primary energy-consuming process in the cell. Therefore, under hypoxic conditions, rapid inhibition of global mRNA translation represents a major protective strategy to maintain energy metabolism. How some mRNAs, especially those that encode crucial survival factors, continue to be efficiently translated in hypoxia is not completely understood. By comparing specific transcript levels in ribonucleoprotein complexes, cytoplasmic polysomes and endoplasmic reticulum (ER)-bound ribosomes, we show that the synthesis of proteins encoded by hypoxia marker genes is favoured at the ER in hypoxia. Gene expression profiling revealed that transcripts particularly increased by the HIF-1 transcription factor network show hypoxia-induced enrichment at the ER. We found that mRNAs favourably translated at the ER have higher conservation scores for both the 5'- and 3'-untranslated regions (UTRs) and contain less upstream initiation codons (uAUGs), indicating the significance of these sequence elements for sustained mRNA translation under hypoxic conditions. Furthermore, we found enrichment of specific cis-elements in mRNA 5'- as well as 3'-UTRs that mediate transcript localization to the ER in hypoxia. We conclude that transcriptome partitioning between the cytoplasm and the ER permits selective mRNA translation under conditions of energy shortage.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Hypoxia / genetics*
  • Cell Hypoxia / physiology*
  • Cell Line
  • Codon, Initiator
  • Cytoplasm / metabolism
  • Endoplasmic Reticulum / metabolism*
  • Gene Expression
  • Genetic Markers
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / genetics
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
  • Procollagen-Proline Dioxygenase / genetics
  • Procollagen-Proline Dioxygenase / metabolism
  • Protein Biosynthesis
  • Protein Disulfide-Isomerases / genetics
  • Protein Disulfide-Isomerases / metabolism
  • RNA, Messenger / genetics*
  • RNA, Messenger / metabolism*
  • Ribosomes / metabolism
  • Transcriptome


  • Codon, Initiator
  • Genetic Markers
  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • RNA, Messenger
  • P4HA1 protein, human
  • Procollagen-Proline Dioxygenase
  • P4HB protein, human
  • Protein Disulfide-Isomerases