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CNOT1 regulates circadian behaviour through Per2 mRNA decay in a deadenylation-dependent manner

Haytham Mohamed Aly Mohamed1, Akinori Takahashi1, Saori Nishijima1

  • 1Cell Signal Unit, Okinawa Institute of Science and Technology Graduate University, Okinawa, Japan.

RNA Biology
|May 5, 2022
PubMed

Insights

The CCR4-NOT deadenylase complex component CNOT1 regulates circadian rhythms by controlling the stability of Per2 mRNA. CNOT1 deficiency lengthens the circadian period by stabilizing Per2 mRNA.

Area of Science:

  • Chronobiology
  • Molecular Biology
  • Gene Regulation

Background:

  • Circadian clocks govern 24-hour rhythms in physiology and behavior.
  • Post-transcriptional mechanisms, including mRNA stability, are crucial for rhythmic gene expression.
  • Poly(A) tail length modulation is a key mechanism controlling mRNA stability.

Purpose of the Study:

  • To investigate the role of CNOT1, a scaffold protein of the CCR4-NOT deadenylase complex, in the mammalian circadian clock.
  • To elucidate the mechanisms by which CNOT1 influences the expression of core clock genes.

Main Methods:

  • Analysis of CNOT1 expression in the suprachiasmatic nucleus.
  • Phenotypic analysis of CNOT1-deficient mice.
  • Measurement of mRNA poly(A) tail length and stability for clock genes.
  • Investigation of the interaction between CNOT1, BRF1, and Per2 mRNA.

Main Results:

  • CNOT1 is highly expressed in the suprachiasmatic nucleus.
  • CNOT1 deficiency in mice leads to circadian period lengthening and altered clock gene expression, notably Per2.
  • Per2 mRNA showed increased poly(A) tail length and stability in Cnot1-deficient mice.
  • CNOT1 is recruited to Per2 mRNA via BRF1, which oscillates inversely to Per2 mRNA.

Conclusions:

  • CNOT1 plays a significant role in regulating the mammalian circadian clock.
  • CNOT1 tunes circadian rhythms by modulating the stability of Per2 mRNA through poly(A) tail length control.
  • The CNOT1-BRF1-Per2 mRNA axis represents a novel regulatory mechanism in circadian timekeeping.
Keywords:
Deadenylationcircadian rhythmmRNA decaypost-transcriptional regulation

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