RNA demethylation by FTO stabilizes the FOXJ1 mRNA for proper motile ciliogenesis

Area of Science:

• Epigenetics
• Molecular Biology
• Developmental Biology

Background:

• Adenosine N6-methylation (m6A) is a prevalent mRNA modification.
• The physiological roles of m6A demethylation are not fully understood.

Purpose of the Study:

• To investigate the function of the m6A demethylase FTO in motile ciliogenesis.
• To elucidate the molecular mechanisms underlying FTO's role in ciliogenesis.

Main Methods:

• Depletion of Fto in Xenopus laevis embryos.
• Analysis of primary human airway epithelium.
• Assessment of Fto knockout mice models.
• mRNA stability assays and gene expression analysis.

Main Results:

• FTO demethylates and stabilizes FOXJ1 mRNA, a key transcription factor for motile cilia.
• Fto depletion in embryos led to significant motile cilia defects.
• FTO depletion in human airway epithelium caused FOXJ1 mRNA destabilization, loss of ciliated cells, and increased goblet cells.
• Fto knockout mice exhibited asthma-like phenotypes upon allergen challenge due to defective ciliated cells.

Conclusions:

• The m6A demethylase FTO is a conserved regulator of motile ciliogenesis.
• The FTO-FOXJ1 axis plays a critical role in both embryonic development and homeostatic maintenance of motile cilia.
• Dysregulation of this axis contributes to airway diseases like asthma.