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PreprintCited by 28RNA and protein synthesis mechanismsPluripotent Stem Cells ResearchDevelopmental Biology and Gene Regulation

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eIF4A2 targets developmental potency and histone H3.3 transcripts for translational control of stem cell pluripotency

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Li, Dan, Yang, Jihong, Huang, Xin, Zhou, Hongwei, Wang, Jianlong·2021·Science Advances
DOI 10.1101/2021.12.24.474136PMC PMC8967233

Preprint — published as 10.1126/sciadv.abm0478 · Paper page

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Abstract

Translational control has emerged as a fundamental regulatory layer of proteome complexity that governs cellular identity and functions. As initiation is the rate-limiting step of translation, we carried out an RNAi screen for key translation initiation factors required to maintain embryonic stem cell (ESC) identity. We identified eIF4A2 and defined its mechanistic action through Rps26-independent and -dependent ribosomes in translation initiation activation of mRNAs encoding pluripotency factors and the histone variant H3.3 with demonstrated roles in maintaining stem cell pluripotency. eIF4A2 also mediates translation initiation activation of Ddx6, which acts together with eIF4A2 to restrict the totipotent 2-cell transcription program in ESCs through Zscan4 mRNA degradation and translation repression. Accordingly, knockdown of eIF4A2 disrupts ESC proteome causing the loss of ESC identity. Collectively, we establish a translational paradigm of the protein synthesis of pluripotency transcription factors and epigenetic regulators imposed on their established roles in controlling pluripotency.

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Metadata

Authors
Li, D., Yang, J., Huang, X., Zhou, H., & Wang, J.
Affiliations
Columbia University Irving Medical Center (US)
Corresponding author
Wang, Jianlong
ORCID
Venue
Science Advances
Publisher
openRxiv
Published
2021-12-25
Volume
8
Issue
13
Pages
eabm0478-eabm0478
ISSN
2375-2548 (ISSN-L)
DOI
10.1101/2021.12.24.474136
PMC
PMC8967233
OpenAlex
W4226211390
Cited by
28
References
1
Citations by year
2026: 1 · 2025: 5 · 2024: 14 · 2023: 5 · 2022: 3
FWCI
2.29
Type
journal article
Language
en
Open access
Licence
cc-by-nc
Locations
  • Science Advances (publishedVersion, cc-by-nc)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
Funders
  • National Institute of General Medical Sciences (R01GM129157)
  • National Center for Research Resources (S10RR027050)
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD097268, R01HD095938)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
Keywords
EIF4A2, translational regulation, embryonic stem cell pluripotency, histone H3.3, translation initiation, DDX6, Zscan4, mRNA degradation, totipotency, stem cell identity, pluripotency transcription factors, epigenetic regulators
MeSH terms
Cell Differentiation, Histones, Peptide Initiation Factors, RNA Stability, Embryonic Stem Cells

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