Ribosome profiling uncovers selective mRNA translation associated with eIF2 phosphorylation in erythroid progenitors

PLoS One. 2018 Apr 10;13(4):e0193790. doi: 10.1371/journal.pone.0193790. eCollection 2018.

Abstract

The regulation of translation initiation factor 2 (eIF2) is important for erythroid survival and differentiation. Lack of iron, a critical component of heme and hemoglobin, activates Heme Regulated Inhibitor (HRI). This results in phosphorylation of eIF2 and reduced eIF2 availability, which inhibits protein synthesis. Translation of specific transcripts such as Atf4, however, is enhanced. Upstream open reading frames (uORFs) are key to this regulation. The aim of this study is to investigate how tunicamycin treatment, that induces eIF2 phosphorylation, affects mRNA translation in erythroblasts. Ribosome profiling combined with RNA sequencing was used to determine translation initiation sites and ribosome density on individual transcripts. Treatment of erythroblasts with Tunicamycin (Tm) increased phosphorylation of eIF2 2-fold. At a false discovery rate of 1%, ribosome density was increased for 147 transcripts, among which transcriptional regulators such as Atf4, Tis7/Ifrd1, Pnrc2, Gtf2h, Mbd3, JunB and Kmt2e. Translation of 337 transcripts decreased more than average, among which Dym and Csde1. Ribosome profiling following Harringtonine treatment uncovered novel translation initiation sites and uORFs. Surprisingly, translated uORFs did not predict the sensitivity of transcripts to altered ribosome recruitment in presence or absence of Tm. The regulation of transcription and translation factors in reponse to eIF2 phosphorylation may explain the large overall response to iron deficiency in erythroblasts.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Bacterial Agents / pharmacology
  • Erythroid Precursor Cells / drug effects
  • Erythroid Precursor Cells / metabolism*
  • Eukaryotic Initiation Factor-2 / metabolism*
  • Mice
  • Open Reading Frames
  • Phosphorylation / drug effects
  • Protein Biosynthesis
  • Ribosomes / drug effects
  • Ribosomes / metabolism*
  • Tunicamycin / pharmacology

Substances

  • Anti-Bacterial Agents
  • Eukaryotic Initiation Factor-2
  • Tunicamycin

Grants and funding

This work was funded by the Landsteiner Foundation for Bloodtransfusion Research (LSBR) www.lsbr.nl [projects 1140 and 1239 to MvL]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.