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Determining Genome-wide Transcript Decay Rates in Proliferating and Quiescent Human Fibroblasts
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ZFP36-mediated mRNA decay regulates metabolism.

Andrew C Cicchetto1, Elsie C Jacobson1, Hannah Sunshine2

  • 1Department of Biological Chemistry, University of California, Los Angeles (UCLA), Los Angeles, CA, USA.

Cell Reports
|April 22, 2023
PubMed
Summary

Growth factors rewire cellular metabolism, but post-transcriptional regulation remains unclear. This study identifies ZFP36 proteins as key regulators of mRNA decay, impacting metabolic enzymes and nutrient transporters during growth factor signaling.

Keywords:
CP: MetabolismCP: Molecular biologyRNA-binding proteinsgrowth factor signalingmRNA stabilitymetabolism

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Area of Science:

  • Molecular Biology
  • Cellular Metabolism
  • Gene Regulation

Background:

  • Cellular metabolism is dynamically regulated by growth factor signaling to support cell growth and proliferation.
  • While transcriptional and post-translational regulation are understood, the role of post-transcriptional mechanisms, specifically mRNA stability, in this process is less defined.

Purpose of the Study:

  • To investigate the role of post-transcriptional regulation, particularly mRNA decay, in growth factor-induced metabolic rewiring.
  • To identify specific RNA-binding proteins and mRNA decay factors involved in this process downstream of growth factor signaling.

Main Methods:

  • Quantitative analysis of mRNA bound by ZFP36 proteins after growth factor stimulation.
  • Assessment of ZFP36's direct impact on the mRNA decay of specific metabolic genes, such as Enolase 2 (Eno2).
  • In vivo validation of the ZFP36/Eno2 axis in VEGF-stimulated retinal angiogenesis.

Main Results:

  • The ZFP36/L1/L2 family of RNA-binding proteins and mRNA decay factors were identified as critical regulators.
  • A comprehensive catalog of metabolic enzyme and nutrient transporter mRNAs directly bound by ZFP36 was generated.
  • ZFP36 was shown to directly induce the decay of Enolase 2 (Eno2) mRNA, affecting protein levels and enzymatic activity.
  • Evidence for a functional ZFP36/Eno2 axis was observed in developmental retinal angiogenesis.

Conclusions:

  • ZFP36-mediated mRNA decay represents a significant post-transcriptional mechanism controlling cellular metabolism.
  • This regulatory pathway is active downstream of acute growth factor signaling, particularly in dynamic cellular and tissue environments.