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<p>Cell fate decisions require tight regulation of gene expression. In planarians, highly regenerative flatworms, the mRNA modification N⁶-methyladenosine (m⁶A) modulates progenitor production and fate. However, the mechanisms governing m⁶A deposition in the planarian transcriptome, and the role of their expanded family of YTHDF m⁶A reader proteins in orchestrating biological functions, remain unclear. Here, we generated the first single-nucleotide resolution map of m⁶A in planarians, and revealed that simple sequence rules guide m⁶A deposition, facilitating the flexible evolutionary gain and loss of these marks. Functional analyses of the five YTHDF planarian m⁶A readers revealed that while individual reader expression is dispensable, together, the planarian YTHDF proteins regulate the production of specific progenitor lineages and overall body size. Collectively, our findings uncover a robust, redundant regulatory architecture for cell fate control in planarians, characterized by multiple m⁶A sites per gene and coordinated m⁶A reader expression. This architecture is essential for proper lineage resolution and provides insights into the evolutionary dynamics of the m⁶A landscape.</p>

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Single-nucleotide m⁶A mapping uncovers redundant YTHDF function in planarian progenitor fate selection

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年1月3日

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  • Yarden Yesharim,
  • Ophir Shwarzbard,
  • Jenny Barboy-Smoliarenko,
  • Prakash Varkey Cherian,
  • Ran Shachar,
  • Amrutha Palavalli,
  • Hanh Thi-Kim Vu,
  • Schraga Schwartz,
  • Omri Wurtzel

摘要

Cell fate decisions require tight regulation of gene expression. In planarians, highly regenerative flatworms, the mRNA modification N⁶-methyladenosine (m⁶A) modulates progenitor production and fate. However, the mechanisms governing m⁶A deposition in the planarian transcriptome, and the role of their expanded family of YTHDF m⁶A reader proteins in orchestrating biological functions, remain unclear. Here, we generated the first single-nucleotide resolution map of m⁶A in planarians, and revealed that simple sequence rules guide m⁶A deposition, facilitating the flexible evolutionary gain and loss of these marks. Functional analyses of the five YTHDF planarian m⁶A readers revealed that while individual reader expression is dispensable, together, the planarian YTHDF proteins regulate the production of specific progenitor lineages and overall body size. Collectively, our findings uncover a robust, redundant regulatory architecture for cell fate control in planarians, characterized by multiple m⁶A sites per gene and coordinated m⁶A reader expression. This architecture is essential for proper lineage resolution and provides insights into the evolutionary dynamics of the m⁶A landscape.