2. Academic Validation
  3. RNA m6A dynamics promote transcription and RNA stability of bivalent genes during iPSC-induced generation of human lung progenitors

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

  • Cell Rep. 2025 Jun 24;44(6):115802. doi: 10.1016/j.celrep.2025.115802.
Shenghua Dong 1,  Junjie Pang 2,  Yushuai Wang 3,  Le Han 4,  Xiaoxiao Zhou 3,  Feng Huang 3,  Subo Zhang 1,  Ning Ma 5,  Huilin Huang 6,  Hengyou Weng 7
Affiliations

Affiliations

  • 1 State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China.
  • 2 MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, China; Guangzhou National Laboratory, Guangzhou, China.
  • 3 Guangzhou National Laboratory, Guangzhou, China.
  • 4 Guangzhou National Laboratory, Guangzhou, China; The Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
  • 5 Guangzhou National Laboratory, Guangzhou, China; School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China. Electronic address: ma_ning@gzlab.ac.cn.
  • 6 State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China. Electronic address: huanghl1@sysucc.org.cn.
  • 7 Guangzhou National Laboratory, Guangzhou, China; The First Affiliated Hospital, The Fifth Affiliated Hospital, State Key Laboratory of Respiratory Diseases, Guangzhou Medical University, Guangzhou, China. Electronic address: weng_hengyou@gzlab.ac.cn.
PMID: 40483690 DOI: 10.1016/j.celrep.2025.115802
Abstract

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.

Keywords

CP: Molecular biology; CP: Stem cell research; IGF2BP2; N(6)-methyladenosine modifications; PRC2; Polycomb repressive complex 2; YTH domain-containing protein 1; YTHDC1; bivalent genes; insulin like growth factor 2 mRNA-binding protein 2; lung endoderm specification; m(6)A modifications.

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