METTL3 and METTL14 determine human neural fate specifications

METTL3/METTL14, the canonical methyltransferase complex modifying N6-methyladenosine (m6A) on mRNAs, plays critical roles in development and various diseases. However, its precise functions in specifying neural fate from human embryonic stem cells (hESCs) remain poorly understood. Here, we demonstrate, using an inducible knockout system, that METTL3/METTL14 deletion impairs the generation of neural progenitor cells (NPCs) from hESCs. Furthermore, inducible METTL3/METTL14-deficient NPCs exhibit compromised long-term proliferation and fail to differentiate into neurons. Mechanistically, METTL3 is enriched in gene loci essential for neurogenesis and chromatin remodeling in human NPCs, thereby promoting chromatin accessibility at these sites. Importantly, forced expression of BRM, a catalytic component of the chromatin-remodeling BAF complex, in METTL3-deficient hESCs rescues the defects in neural fate specifications caused by METTL3 loss. Our study systematically defines the essential requirement of METTL3 and METTL14 in ensuring the fidelity and neuronal specification of human NPCs, and underscores the coordination among distinct epigenetic regulators in neural development.