METTL3 and METTL14 determine human neural fate specifications

Area of Science:

• Epigenetics
• Developmental Biology
• Stem Cell Biology

Background:

• The METTL3/METTL14 complex catalyzes N6-methyladenosine (m6A) modification on mRNAs, impacting cellular processes.
• The role of METTL3/METTL14 in specifying neural fate from human embryonic stem cells (hESCs) is not well understood.

Purpose of the Study:

• To investigate the function of the METTL3/METTL14 complex in neural fate specification from hESCs.
• To elucidate the molecular mechanisms by which METTL3/METTL14 regulates neurogenesis.

Main Methods:

• Utilized an inducible knockout system to delete METTL3/METTL14 in hESCs.
• Analyzed the effects of METTL3/METTL14 deficiency on neural progenitor cell (NPC) generation, proliferation, and differentiation.
• Investigated the enrichment of METTL3 in gene loci related to neurogenesis and chromatin remodeling.
• Assessed the impact of METTL3 loss on chromatin accessibility.
• Examined the rescue effect of BRM (BAF complex component) expression in METTL3-deficient cells.

Main Results:

• METTL3/METTL14 deletion significantly impairs NPC generation from hESCs.
• METTL3/METTL14-deficient NPCs show reduced long-term proliferation and failed neuronal differentiation.
• METTL3 localizes to neurogenesis-related gene loci in human NPCs, promoting chromatin accessibility.
• Forced expression of BRM rescues neural fate specification defects in METTL3-deficient hESCs.

Conclusions:

• METTL3 and METTL14 are essential for the fidelity and neuronal specification of human NPCs.
• The METTL3/METTL14 complex regulates neurogenesis through chromatin remodeling and accessibility.
• This study highlights the interplay between METTL3/METTL14 and other epigenetic regulators in human neural development.