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Global miRNA dosage control of embryonic germ layer specification

Author

Listed:
  • Yingzi Cui

    (Peking University)

  • Xuehui Lyu

    (Peking University)

  • Li Ding

    (Peking University)

  • Lan Ke

    (Peking University
    Peking University
    Peking University)

  • Dechang Yang

    (Peking University
    Peking University
    Peking University)

  • Mehdi Pirouz

    (Boston Children’s Hospital
    Harvard Medical School)

  • Ye Qi

    (Peking University)

  • Jennie Ong

    (Peking University
    Peking University)

  • Ge Gao

    (Peking University
    Peking University
    Peking University)

  • Peng Du

    (Peking University
    Peking University)

  • Richard I. Gregory

    (Boston Children’s Hospital
    Harvard Medical School
    Harvard Stem Cell Institute
    Harvard Medical School)

Abstract

MicroRNAs (miRNAs) have essential functions during embryonic development, and their dysregulation causes cancer1,2. Altered global miRNA abundance is found in different tissues and tumours, which implies that precise control of miRNA dosage is important1,3,4, but the underlying mechanism(s) of this control remain unknown. The protein complex Microprocessor, which comprises one DROSHA and two DGCR8 proteins, is essential for miRNA biogenesis5–7. Here we identify a developmentally regulated miRNA dosage control mechanism that involves alternative transcription initiation (ATI) of DGCR8. ATI occurs downstream of a stem-loop in DGCR8 mRNA to bypass an autoregulatory feedback loop during mouse embryonic stem (mES) cell differentiation. Deletion of the stem-loop causes imbalanced DGCR8:DROSHA protein stoichiometry that drives irreversible Microprocessor aggregation, reduced primary miRNA processing, decreased mature miRNA abundance, and widespread de-repression of lipid metabolic mRNA targets. Although global miRNA dosage control is not essential for mES cells to exit from pluripotency, its dysregulation alters lipid metabolic pathways and interferes with embryonic development by disrupting germ layer specification in vitro and in vivo. This miRNA dosage control mechanism is conserved in humans. Our results identify a promoter switch that balances Microprocessor autoregulation and aggregation to precisely control global miRNA dosage and govern stem cell fate decisions during early embryonic development.

Suggested Citation

  • Yingzi Cui & Xuehui Lyu & Li Ding & Lan Ke & Dechang Yang & Mehdi Pirouz & Ye Qi & Jennie Ong & Ge Gao & Peng Du & Richard I. Gregory, 2021. "Global miRNA dosage control of embryonic germ layer specification," Nature, Nature, vol. 593(7860), pages 602-606, May.
    • Handle: RePEc:nat:nature:v:593:y:2021:i:7860:d:10.1038_s41586-021-03524-0
    DOI: 10.1038/s41586-021-03524-0
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    Cited by:

    1. Xiaowen Shi & Hua Yang & Chen Chen & Jie Hou & Tieming Ji & Jianlin Cheng & James A. Birchler, 2022. "Dosage-sensitive miRNAs trigger modulation of gene expression during genomic imbalance in maize," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    2. Qing Li & Jiansen Lu & Xidi Yin & Yunjian Chang & Chao Wang & Meng Yan & Li Feng & Yanbo Cheng & Yun Gao & Beiying Xu & Yao Zhang & Yingyi Wang & Guizhong Cui & Luang Xu & Yidi Sun & Rong Zeng & Yixue, 2023. "Base editing-mediated one-step inactivation of the Dnmt gene family reveals critical roles of DNA methylation during mouse gastrulation," Nature Communications, Nature, vol. 14(1), pages 1-19, December.

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