METTL3 and METTL14 determine human neural fate specifications
Year: 2025
Type: article
Abstract: 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.
Source: Nucleic Acids Research
DOI: 10.1093/nar/gkaf1397
Authors: Yanqi Zhang, Jitian Zhang, Huaisong Lin, Junwei Wang, Qianyu Chen, Tiancheng Zhou, Qi Xing, Guangjin Pan, Yongli Shan
Language: English
Topic: RNA modifications and cancer
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,992
Funders: National Natural Science Foundation of China, Chinese Academy of Sciences, Youth Innovation Promotion Association of the Chinese Academy of Sciences, National Key Research and Development Program of China, Science and Technology Planning Project of Guangdong Province, Youth Innovation Promotion Association, National Key Research and Development Program of China Stem Cell and Translational Research, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences
OpenAlex ID: W4417303124