Fto-mediated m⁶A modification is essential for cerebellar development through regulating epigenetic reprogramming.

Area of Science:

• Neuroscience
• Epigenetics
• Molecular Biology

Background:

• Epitranscriptomic regulation, particularly m⁶A methylation, is crucial for cerebellar development and function.
• The specific role of the RNA demethylase Fto in the cerebellum remains unclear.

Purpose of the Study:

• To investigate the function of Fto in cerebellar development and function using a knockout mouse model.
• To elucidate the molecular mechanisms underlying Fto's role in cerebellar development.

Main Methods:

• Generated Fto knockout (Fto^KO) mice for phenotypic analysis.
• Assessed cerebellar function via behavioral tests and Nissl staining.
• Utilized molecular techniques including immunofluorescence, m⁶A-RIP-seq, ATAC-seq, CUT&Tag-seq, and Co-IP to analyze gene expression, m⁶A levels, and chromatin accessibility.

Main Results:

• Fto^KO mice displayed cerebellar ataxia with tremors and abnormal gait.
• Reduced FTO expression led to altered expression of neuronal development and self-renewal genes.
• Mechanistically, Fto loss resulted in Kat8 upregulation, increased m⁶A levels, and altered H4K16ac modification, impacting chromatin accessibility.

Conclusions:

• Fto plays a critical role in cerebellar development.
• Fto deficiency disrupts cerebellar function through m⁶A-dependent regulation of Kat8 and chromatin accessibility.
• These findings highlight the importance of epitranscriptomic regulation in neurodevelopmental processes.