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

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

doi:10.1038/s44318-025-00662-3

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

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

^*Corresponding author for this work

Department of Molecular Genetics

Research output: Contribution to journal › Article › peer-review

Abstract

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.

Original language	English
Journal	EMBO Journal
DOIs	https://doi.org/10.1038/s44318-025-00662-3
Publication status	Published - 3 Jan 2026

Funding

We thank Hila Kobo and Tamar Katzir for assistance with Illumina sequencing at the Tel Aviv University core facilities. We thank Rami Khosravi for assistance with scRNAseq library preparation at the Tel Aviv University single cell core unit. We thank Kristina Karin Mirkes for support in confocal microscopy imaging. We thank Prof. Joel Hirsch and Dr. Aldema Sas-Chen for critical input on the manuscript. We thank the Wurtzel lab for critical input. OW is supported by the Israel Science Foundation (grant 2039/18) and the European Research Council (no. 853640). OW is a Zuckerman Faculty Scholar. AP is supported by the EIPOD-LinC Postdoc Fellowship from the European Molecular Biology Laboratory. HTKV is supported by the European Molecular Biology Laboratory.

All Science Journal Classification (ASJC) codes

General Neuroscience
Molecular Biology
General Biochemistry,Genetics and Molecular Biology
General Immunology and Microbiology

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10.1038/s44318-025-00662-3Licence: CC BY

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title = "Single-nucleotide m⁶A mapping uncovers redundant YTHDF function in planarian progenitor fate selection",

abstract = "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.",

author = "Yarden Yesharim and Ophir Shwarzbard and Jenny Barboy-Smoliarenko and Cherian, \{Prakash Varkey\} and Ran Shachar and Amrutha Palavalli and Vu, \{Hanh Thi Kim\} and Schraga Schwartz and Omri Wurtzel",

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AU - Yesharim, Yarden

AU - Shwarzbard, Ophir

AU - Barboy-Smoliarenko, Jenny

AU - Cherian, Prakash Varkey

AU - Shachar, Ran

AU - Palavalli, Amrutha

AU - Vu, Hanh Thi Kim

AU - Schwartz, Schraga

AU - Wurtzel, Omri

PY - 2026/1/3

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N2 - 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.

AB - 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.

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JO - EMBO Journal

JF - EMBO Journal

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

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