METTL3 shapes m6A epitranscriptomic landscape for successful human placentation

Area of Science:

• Reproductive Biology
• Epigenetics
• Cell Biology

Background:

• Methyltransferase-like 3 (METTL3) is essential for mammalian development.
• The role of METTL3 in human placentation is largely unknown.
• RNA m6A methylation is a key epitranscriptomic modification.

Purpose of the Study:

• To investigate the role of METTL3 in human placentation.
• To determine the impact of METTL3 dysregulation on pregnancy outcomes.
• To elucidate the molecular mechanisms by which METTL3 influences trophoblast function.

Main Methods:

• Analysis of METTL3 expression in human placental tissues from pregnancies with adverse outcomes.
• Loss-of-function and gain-in-function studies in human trophoblast stem cells (TSCs).
• Global RNA m6A profiling and RNA-binding analyses.
• Conditional deletion of METTL3 in mouse trophoblast progenitors.

Main Results:

• A balance of METTL3 in trophoblast cells is critical for successful human placentation.
• Loss of METTL3 in trophoblast progenitors is linked to recurrent pregnancy loss and preterm birth.
• METTL3 is upregulated in fetal growth restriction (FGR).
• METTL3 is essential for TSC self-renewal and differentiation into extravillous trophoblast cells (EVTs).
• METTL3 loss promotes syncytiotrophoblast (STB) development.
• METTL3 regulates m6A modification of key trophoblast regulator mRNAs (e.g., GATA2, GATA3, TEAD1).
• METTL3 deletion in mouse trophoblast progenitors arrests self-renewal.
• METTL3 acts as a conserved epitranscriptomic governor in trophoblast progenitors.

Conclusions:

• METTL3 plays a critical, conserved role in human placentation.
• METTL3 regulates trophoblast progenitor self-renewal and differentiation fate.
• Dysregulation of METTL3 contributes to adverse pregnancy outcomes.