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eIF4A2 targets developmental potency and histone H3.3 transcripts for translational control of stem cell pluripotency
Dan Li1,2,3, Jihong Yang1, Xin Huang1
1Department of Medicine, Columbia Center for Human Development, Columbia Stem Cell Initiative, Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY 10032, USA.
Science Advances
|March 30, 2022
Summary
Eukaryotic translation initiation factor 4A2 (eIF4A2) is crucial for embryonic stem cell (ESC) identity by regulating pluripotency factor translation. Loss of eIF4A2 disrupts protein synthesis, leading to loss of ESC identity.
Area of Science:
- Cell Biology
- Molecular Biology
- Epigenetics
Background:
- Translational control is a key regulator of proteome complexity and cellular functions.
- Translation initiation is the rate-limiting step in protein synthesis.
- Embryonic stem cell (ESC) identity relies on precise regulation of gene expression.
Purpose of the Study:
- To identify key translation initiation factors essential for maintaining ESC identity.
- To elucidate the mechanism by which eIF4A2 regulates pluripotency.
- To understand the role of eIF4A2 in restricting the totipotent two-cell program.
Main Methods:
- RNA interference (RNAi) screen for translation initiation factors in ESCs.
- Mechanistic studies on eIF4A2 function using ribosome-dependent and -independent pathways.
- Analysis of mRNA degradation and translation repression involving Ddx6 and Zscan4.
Main Results:
- eIF4A2 was identified as a critical factor for ESC identity.
- eIF4A2 activates translation of mRNAs encoding pluripotency factors and H3.3.
- eIF4A2 and Ddx6 cooperate to repress the two-cell transcription program by degrading Zscan4 mRNA.
Conclusions:
- eIF4A2 plays a vital role in maintaining ESC identity through translational control of pluripotency factors and epigenetic regulators.
- Disruption of eIF4A2 function leads to proteome imbalance and loss of ESC identity.
- This study establishes a translational control paradigm for stem cell pluripotency.
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