METTL3 mediated epitranscriptomic regulation safeguards the specification of neural cell fate from human embryonic stem cells

Human brain development relies on precisely orchestrated cell fate decisions, through which pluripotent stem cells are transformed into diverse neural lineages. N6-methyladenosine, the most abundant internal RNA modification, has emerged as a pivotal regulator of this process by regulating neural stem cell fate determination, neuronal differentiation, synaptic plasticity and glial cell function. Aberrant m6A modification is linked to various neurological diseases. Nevertheless, the molecular mechanisms governing human neural fate specification remain poorly understood. Here, we systematically delineate the m6A modification landscapes during human embryonic stem cell differentiation, and identify METTL3 as a critical regulator of neural lineage commitment. Utilizing brain organoid models, we demonstrate that METTL3 knockout severely impairs the in vitro development of brain organoid. This impairment is characterized by the entrapment of neural progenitor cells in a cycling state, a reduction in intermediate progenitor cells, and defects in neuronal differentiation, most notably, the premature and excessive generation of inhibitory neurons accompanied by a decrease in excitatory neurons.