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

Area of Science:

• Molecular Biology
• Developmental Biology
• Regenerative Biology

Background:

• Cell fate decisions are crucial for development and regeneration, requiring precise gene expression regulation.
• The mRNA modification N⁶-methyladenosine (m⁶A) plays a role in progenitor production and fate in planarians, a highly regenerative flatworm.
• Mechanisms of m⁶A deposition and the function of YTHDF m⁶A reader proteins in planarians are not well understood.

Purpose of the Study:

• To map the N⁶-methyladenosine (m⁶A) landscape in planarians at single-nucleotide resolution.
• To investigate the functional roles of the planarian YTHDF m⁶A reader proteins in regulating biological processes.
• To elucidate the regulatory architecture governing m⁶A deposition and its impact on cell fate.

Main Methods:

• Generation of a single-nucleotide resolution map of m⁶A in the planarian transcriptome.
• Bioinformatic analysis to identify sequence rules governing m⁶A deposition.
• Functional analysis of five YTHDF m⁶A reader proteins in planarians.

Main Results:

• m⁶A deposition in planarians follows simple sequence rules, allowing for evolutionary flexibility.
• Individual YTHDF reader expression is dispensable, but the collective action of all five YTHDF proteins regulates progenitor lineage production and body size.
• A robust and redundant regulatory system involving multiple m⁶A sites per gene and coordinated reader expression controls cell fate.

Conclusions:

• Planarian cell fate control is orchestrated by a sophisticated m⁶A-based regulatory network.
• The coordinated action of YTHDF reader proteins is essential for proper lineage resolution and body size regulation in planarians.
• This study provides insights into the evolutionary dynamics of the m⁶A landscape and its role in regeneration.