mRNA stability in response to m6A placement is linked to cell identity in planarians

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 length-dependent variant of the exon junction complex-mediated (EJC) 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 further 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. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=77 SRC="FIGDIR/small/714417v2_ufig1.gif" ALT="Figure 1"> View larger version (29K): org.highwire.dtl.DTLVardef@1dd6a3aorg.highwire.dtl.DTLVardef@1693e2forg.highwire.dtl.DTLVardef@71b2a6org.highwire.dtl.DTLVardef@87b9bf_HPS_FORMAT_FIGEXP M_FIG C_FIG