METTL3-mediated Epitranscriptomic Regulation Safeguards the Specification of Neural Cell Fate From Human Embryonic Stem Cells

N6-methyladenosine (m6A), the most abundant internal RNA modification, has emerged as a pivotal regulator neurodevelopment and neurological diseases. However, the molecular mechanisms governing the specification of human neural fate remain poorly understood.

Here, we systematically delineate the m6A modification landscapes during the differentiation of human embryonic stem cells (ESCs), and identify METTL3 as a critical regulator of neural lineage commitment. Utilizing brain organoid models, we demonstrate that METTL3 knockout severely impairs the development of brain organoids with excessive generation of inhibitory neurons accompanied by a decrease in excitatory neurons, a phenotype associated with neurological disorders.