YTHDC1 recognizes METTL16-dependent m <sup>6</sup> A on caRNAs and coordinates cotranscriptional splicing
Abstract
N 6 -methyladenosine (m 6 A) RNA modification regulates diverse biological process. The m 6 A writers and downstream readers collaboratively undertake m 6 A-mediated RNA metabolism, yet the functional specificity among different writers and readers remains poorly understood. Using limb organogenesis as a development model, we uncover a critical and specific functional axis between the m 6 A reader YTHDC1 and writer METTL16. Depletion of either YTHDC1 or METTL16-but not METTL3-causes severe limb malformations, revealing unexpected functional selectivity. Mechanistically, we demonstrate that YTHDC1 specifically recognizes METTL16-deposited m 6 A marks on chromatin-associated RNAs, orchestrating cotranscriptional splicing of genes vital for cell cycle progression and DNA repair. Loss of YTHDC1 triggers genome-wide transcription arrest and dysregulates key developmental gene expression programs. Importantly, chromatin-bound YTHDC1 recruits splicing factors to transcriptional complex through liquid–liquid phase separation (LLPS), with alkalic arginine residues in its C-terminal region being molecular determinants. Our findings identified a selective and specific METTL16-m 6 A-YTHDC1 axis that couples RNA modification with cotranscriptional splicing during mammalian organogenesis, providing molecular insights into how epitranscriptomic regulation governs developmental decisions.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (14)
Zhong Zhang
Department of Implantology, State Key Laboratory of Oral Diseases and National Center for Stomatology and National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University
Qi Yin
School of Materials Science and Engineering
Weimin Lin
Department of Implantology, State Key Laboratory of Oral Diseases and National Center for Stomatology and National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University
Qiwen Li
Department of Implantology, State Key Laboratory of Oral Diseases and National Center for Stomatology and National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University
Rui Sheng
Department of Implantology, State Key Laboratory of Oral Diseases and National Center for Stomatology and National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University
Shuang Jiang
Key Laboratory of Precision and Intelligent Chemistry, School of Chemistry and Materials Science
Kexin Lei
Tsinghua-Peking Center for Life Sciences, Tsinghua University
Linfeng Liu
Department of Implantology, The Affiliated Stomatological Hospital of Nanjing Medical University, Jiangsu Province Key Laboratory of Oral Diseases, Nanjing Medical University
Lanxin Zhang
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University
Chunlin Qian
Department of Implantology, State Key Laboratory of Oral Diseases and National Center for Stomatology and National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University
Junru Wen
Department of Implantology, Stomatology Hospital, Zhejiang University School of Medicine
Zirui Wang
State Key Laboratory of Structural Chemistry
Chong Chen
Department of Thoracic Oncology, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University
Quan Yuan