RNA m⁶A dynamics promote transcription and RNA stability of bivalent genes during iPSC-induced generation of human...

RNA N⁶-methyladenosine (m⁶A) modifications play a crucial role in the control of RNA synthesis and metabolism during embryonic development. However, the m⁶A landscape and its impact on early embryonic lung development remain elusive. In this study, we uncover the dynamic and stage-specific patterns of the m⁶A methylome that correlate with gene expression changes during the differentiation of human induced pluripotent stem cells (iPSCs) into lung progenitors (LPs). Mechanistically, RNA binding motif protein 15B (RBM15B) is upregulated and enhances m⁶A modification in differentiated cells. Concurrently, the loss of the m⁶A reader YTH domain-containing protein 1 (YTHDC1) alleviates Polycomb repressive complex 2 (PRC2)-mediated transcriptional silencing of bivalent genes such as GATA4, GATA6, and EOMES. Moreover, the upregulation of another m⁶A reader, insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2), further stabilizes these messenger RNA (mRNA) transcripts. The switch of m⁶A readers coordinates chromatin remodeling and post-transcriptional regulation to drive lung endoderm specification. This study highlights the delicate m⁶A-centered regulatory mechanisms and the indispensable role of m⁶A modification in the early stages of embryonic lung development.