Year: 2025
Type: article
Abstract: METTL3 is a key regulator of RNA metabolism, yet its genomic and epitranscriptomic roles in tissue development are largely unexplored. Using embryonic stem cell-derived 3D retinal organoids to model retinal progenitor cell (RPC) differentiation, we integrated transcriptome-wide m6A profiling (GLORI), protein-DNA (chromatin immunoprecipitation sequencing [ChIP-seq] and CUT&RUN) and chromatin accessibility (ATAC-seq) mapping, and targeted m6A engineering (dCas13b-FTO) to dissect METTL3 function. Loss of METTL3 nuclear m6A activity disrupted Rx+ retinal anlage formation in vitro, with dCas13b-FTO epitranscriptome engineering revealing that m6A at the Six3 3'UTR governs its stability. Surprisingly, while METTL3 loss altered histone modifications and chromatin accessibility, its direct chromatin targets showed little transcriptional correlation. A degron-based METTL3 degradation strategy, paired with protein-RNA interaction profiling, exposed rapid regulatory shifts in RPCs, revealing a METTL3-Ythdf1 protein-RNA axis. Our multi-omics approach establishes METTL3-dependent m6A as a critical epitranscriptomic layer in retinal development, unveiling a genomic paradigm in which chromatin accessibility diverges from transcriptional output.
Source: Stem Cell Reports
Authors: Jing Xu, Yuanhao Huang, Zhaowei Han, Qiang Li, Jie Liu, Rajesh C. Rao
Institutions: University of Michigan, Michigan Medicine
Language: English
Topic: RNA modifications and cancer
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $4,190
Funders: March Hoops to BEAT Blindness, Foundation for the National Institutes of Health, Research to Prevent Blindness, A. Alfred Taubman Medical Research Institute, Beatrice and Reymont Paul Foundation, National Human Genome Research Institute, National Eye Institute, National Institute of General Medical Sciences
OpenAlex ID: W4415478789