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A Reverse Genetic Approach to Test Functional Redundancy During Embryogenesis
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Global miRNA dosage control of embryonic germ layer specification

Yingzi Cui1, Xuehui Lyu2, Li Ding1

  • 1MOE Key Laboratory of Cell Proliferation and Differentiation, School of Life Sciences, Peking University, Beijing, China.

Nature
|May 6, 2021
PubMed

Insights

A novel mechanism controlling microRNA (miRNA) dosage involves alternative transcription initiation of DGCR8, crucial for embryonic development. This process balances Microprocessor complex function, preventing aggregation and ensuring proper miRNA levels for stem cell fate.

Area of Science:

  • Developmental Biology
  • Molecular Biology
  • Genetics

Background:

  • MicroRNAs (miRNAs) are vital for embryonic development and cancer, yet the mechanisms controlling their abundance remain unclear.
  • The Microprocessor complex (DROSHA and DGCR8) is essential for miRNA biogenesis.
  • Altered miRNA levels are observed in various tissues and tumors, highlighting the importance of precise miRNA dosage control.

Purpose of the Study:

  • To identify the mechanism regulating global miRNA abundance during embryonic development.
  • To investigate the role of DGCR8 regulation in controlling miRNA dosage.
  • To understand how miRNA dosage impacts stem cell differentiation and embryonic development.

Main Methods:

  • Investigated alternative transcription initiation (ATI) of DGCR8 in mouse embryonic stem (mES) cells.
  • Utilized genetic deletion of a stem-loop in DGCR8 mRNA to study its effects.
  • Analyzed Microprocessor complex stoichiometry, miRNA processing, mature miRNA abundance, and mRNA target de-repression.
  • Assessed the impact of miRNA dosage dysregulation on mES cell pluripotency exit, lipid metabolism, and germ layer specification in vitro and in vivo.

Main Results:

  • Identified a developmentally regulated miRNA dosage control mechanism involving ATI of DGCR8.
  • Deletion of a DGCR8 stem-loop led to imbalanced DGCR8:DROSHA stoichiometry, Microprocessor aggregation, and reduced miRNA processing.
  • Dysregulation of miRNA dosage altered lipid metabolic pathways and disrupted germ layer specification during embryonic development.
  • The identified miRNA dosage control mechanism is conserved in humans.

Conclusions:

  • A promoter switch involving DGCR8 ATI balances Microprocessor autoregulation and aggregation.
  • This mechanism precisely controls global miRNA dosage, essential for governing stem cell fate decisions.
  • Dysregulation of this miRNA dosage control interferes with embryonic development and is linked to altered lipid metabolism.

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