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

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 (NPCs), 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. Importantly, these findings extend to human 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 and potentially in cancer. Overall design: We perform high-throughput RNA sequencing of cultured neural progenitor/stem cells (NPCs) with or without deletion of VIRMA to profile RNA half-lives. Wiltype (WT) and conditional knockout (cKO) NPCs were treated with actinomycin-D (ActD) to halt new RNA synthesis. At 0, 3, and 6 hours post-treatment, cells were collected for total RNA extraction followed by RNA-seq. Four replicates were conducted for each genotype at each timepoint.