PhD Candidate The University of Hong Kong Hong Kong, Hong Kong
Abstract: Genomic integrity is critical for early embryonic development. Severe genomic instability, including chromosome missegregation and aneuploidy, can lead to miscarriage and developmental abnormalities in humans. However, the molecular mechanisms underlying mitotic defects in early embryos remain poorly understood. Here, we reveal a novel role for METTL3-dependent N6-methyladenosine (m6A) modification in safeguarding DNA replication and cell division, supported by evidence from both pluripotent and trophoblast stem cells, and, importantly, human embryos. METTL3 depletion leads to pervasive polyploidy, cell cycle delay, and compromised proliferation. Mechanistically, m6A modification on centromeric satellite repeats suppresses their transcription and stabilizes CENPA loading during DNA replication. These findings establish the METTL3-satellite repeats-CENPA nexus as a critical regulator of centromeric stability in early human development, providing new insights into the epi-transcriptional control of mitotic fidelity and potential therapeutic avenues for pregnancy complications.
Funding Source: This project is supported by Health@InnoHK, Innovation Technology Commission, HKSAR
