The stability of m⁶A-marked transcripts is linked to cell identity in planarians

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Höhn, Constantin ; Pittroff, Andreas ; Gribling-Burrer, Anne-Sophie ; Hülsmann, Lisa ; Smyth, Redmond P. ; Kuhn, Claus-D.:
The stability of m⁶A-marked transcripts is linked to cell identity in planarians.
In: Nucleic Acids Research. Bd. 54 (2026) Heft 18 . - gkag892.
ISSN 1362-4962
DOI: https://doi.org/10.1093/nar/gkag892

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Abstract

N6-methyladenosine (m6A) is a prevalent internal modification of eukaryotic mRNA that influences transcript fate, including mRNA stability and cell-type-specific gene expression. However, the mechanisms underlying m6A-mediated regulation remain poorly understood in many systems, including the highly regenerative planarian Schmidtea mediterranea. To address this, we generated a high-confidence atlas of ∼72 200 m6A sites across the planarian transcriptome using multiplexed direct RNA sequencing. The m6A sites follow a DRAYW consensus motif and are highly enriched near stop codons while being largely excluded from coding sequences. This pattern aligns with an exon and intron length-dependent variant of the exon junction complex (EJC)-mediated exclusion model, wherein the EJC restricts m6A deposition near splice sites. Knockdown of the m6A writer complex induced pronounced, cell-type-specific changes in transcript stability. Destabilized transcripts were enriched for intestinal markers, whereas stabilized transcripts were associated with neoblasts, the adult stem cells of planarians. Transcriptional shut-off experiments confirmed that m6A has opposing effects on mRNA decay depending on cellular context: it stabilizes transcripts in differentiated cells, while it promotes the degradation of mRNAs associated with neoblasts. Collectively, these results support a model in which cell-type-specific regulation of mRNA stability by m6A plays a crucial role in shaping cell identity in planarians.