METTL3 uncouples chromatin accessibility from transcription during retinal development

Area of Science:

• Developmental Biology
• RNA Biology
• Genomics

Background:

• METTL3 is a key regulator of RNA metabolism, but its roles in tissue development are not well understood.
• Retinal progenitor cell (RPC) differentiation is essential for eye development and requires precise gene regulation.

Purpose of the Study:

• To investigate the genomic and epitranscriptomic functions of METTL3 in retinal development using 3D retinal organoids.
• To dissect the molecular mechanisms by which METTL3 influences RPC differentiation and retinal anlage formation.

Main Methods:

• Integrated multi-omics approach including m6A profiling (GLORI), ChIP-seq, CUT&RUN, ATAC-seq, and targeted epitranscriptome engineering (dCas13b-FTO).
• Utilized degron-based METTL3 degradation and protein-RNA interaction profiling in RPCs.
• Employed 3D retinal organoids derived from embryonic stem cells to model retinal development.

Main Results:

• Loss of METTL3 disrupted retinal anlage formation, demonstrating its critical role in early retinal development.
• m6A modification at the Six3 3'UTR was identified as a key regulator of Six3 mRNA stability.
• METTL3 influenced chromatin accessibility and histone modifications, but direct chromatin targets showed limited transcriptional correlation.
• A METTL3-Ythdf1 protein-RNA axis was revealed, highlighting rapid regulatory shifts in RPCs.

Conclusions:

• METTL3-dependent m6A modification is a critical epitranscriptomic layer in retinal development.
• The study unveils a novel paradigm where chromatin accessibility can diverge from transcriptional output.
• This work provides insights into the complex interplay between epitranscriptomics, genomics, and developmental processes.