YTHDC1 recognizes METTL16-dependent m 6 A on caRNAs and coordinates cotranscriptional splicing

作者：Zhang Zhong, Q H Yin, Weimin Lin, Qi Li, Rui Sheng, Shuang Jiang, Kexin Lei, L. Liu, Lanxin Zhang, Chunlin Qian, Junru Wen, Zirui Wang, Chong Chen, Q Yuan · 发表于：Proceedings of the National Academy of Sciences · 年份：2026 · DOI：10.1073/pnas.2524579123 · 研究领域：RNA modifications and cancer、RNA and protein synthesis mechanisms、RNA Research and Splicing

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.