YTHDC1 recognizes METTL16-dependent m6A on caRNAs and coordinates cotranscriptional splicing
- Proc Natl Acad Sci U S A. 2026 Apr 21;123(16):e2524579123. doi: 10.1073/pnas.2524579123.
- 1. 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, Chengdu, Sichuan 610041, China.
- 2. Department of Implantology, The Affiliated Stomatological Hospital of Nanjing Medical University, Jiangsu Province Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, Jiangsu 210008, China.
- 3. State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China.
- 4. Department of Implantology, Stomatology Hospital, Zhejiang University School of Medicine, Hangzhou 310016, China.
- 5. Daniel J. Epstein Department of Industrial & Systems Engineering, University of Southern California, Los Angeles, CA 90089.
- # Contributed equally.
N6-methyladenosine (m6A) RNA modification regulates diverse biological process. The m6A writers and downstream readers collaboratively undertake m6A-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 m6A 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 m6A 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-m6A-YTHDC1 axis that couples RNA modification with cotranscriptional splicing during mammalian organogenesis, providing molecular insights into how epitranscriptomic regulation governs developmental decisions.