2. Academic Validation
  3. VIRMA-mediated m6A modification regulates forebrain formation through modulating ribosome biogenesis

VIRMA-mediated m6A modification regulates forebrain formation through modulating ribosome biogenesis

  • Sci Adv. 2025 Jun 27;11(26):eadq9643. doi: 10.1126/sciadv.adq9643.
Min Wu 1 2 3 4,  Xiaoli Wu 1 2 4 5,  Haifeng Sun 6,  Wen Wang 1 2 3,  Leyi Zhang 1 2 5,  Xia Liu 1 2 5,  Yifan Zhang 7,  Xinning Zhang 7,  Jun Liu 7,  Bin Shen 6,  Tao Zhou 1 2 3 4
Affiliations

Affiliations

  • 1 Shenzhen Neher Neural Plasticity Laboratory, Shenzhen Key Laboratory of Drug Addiction, the Brain Cognition and Brain Disease Institute, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China.
  • 2 Shenzhen-Hong Kong Institute of Brain Science-Shenzhen Fundamental Research Institutions, Shenzhen 518055, China.
  • 3 CAS Key Laboratory of Brain Connectome and Manipulation, Chinese Academy of Sciences, Shenzhen 518055, China.
  • 4 Faculty of Life and Health Sciences, Shenzhen University of Advanced Technology, Shenzhen 518106, China.
  • 5 University of Chinese Academy of Sciences, Beijing 100049, China.
  • 6 State Key Laboratory of Reproductive Medicine and Offspring Health, Women's Hospital of Nanjing Medical University, Nanjing Maternity and Child Health Care Hospital, Gusu School, Nanjing Medical University, Nanjing 211166, China.
  • 7 State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China.
PMID: 40577453 DOI: 10.1126/sciadv.adq9643
Abstract

N6-Methyladenosine (m6A) modification plays crucial roles in tissue development and homeostasis. However, the mechanisms underlying cellular adaptation of m6A modification and their impact on protein synthesis machinery remain unclear. VIRMA, the largest and evolutionarily conserved core of the m6A methyltransferase complex, is highly expressed in the embryonic brain and various cancers. Here, we demonstrate that VIRMA-mediated m6A modification is essential for active ribosome biogenesis. VIRMA depletion destabilizes the entire writer complex and reduces m6A levels, leading to decreased proliferation and increased Apoptosis of neural progenitor/stem cells, ultimately causing severe forebrain developmental defects. Mechanistically, VIRMA depletion impairs ribosome biogenesis by inhibiting mRNA decay, triggering a p53-dependent stress response and compromising global protein synthesis. These findings extend to some Cancer cells, suggesting a potential conservation of this mechanism. Overall, our study reveals the critical role of m6A in adapting protein synthesis machinery during brain development.

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