Nuclear m6A reader YTHDC1 promotes muscle stem cell activation/proliferation by regulating mRNA splicing and nuclear...

Area of Science:

• Molecular Biology
• Cell Biology
• Regenerative Medicine

Background:

• Skeletal muscle stem cells (satellite cells, SCs) drive muscle regeneration.
• Post-transcriptional regulation, particularly RNA modifications like m6A, plays a key role in SC function.
• The function of m6A reader proteins in SCs is largely unexplored.

Purpose of the Study:

• To investigate the regulatory role of YTHDC1, an m6A reader, in mouse skeletal muscle stem cells.
• To elucidate the mechanisms by which YTHDC1 influences SC activation, proliferation, and muscle regeneration.

Main Methods:

• Utilized LACE-seq for transcriptome-wide profiling of YTHDC1 binding targets.
• Performed splicing and nuclear export analyses to identify mRNA targets.
• Mapped YTHDC1 interacting protein partners in myoblasts.

Main Results:

• YTHDC1 is essential for SC activation and proliferation following muscle injury.
• Inducible depletion of YTHDC1 significantly impairs SC regenerative capacity.
• Identified m6A-mediated binding, splicing, and nuclear export targets of YTHDC1.
• Discovered hnRNPG as a bona fide interacting partner of YTHDC1.

Conclusions:

• YTHDC1 is a critical regulator of skeletal muscle stem cell regenerative function.
• YTHDC1 controls SC regeneration through diverse gene regulatory mechanisms, including mRNA splicing and nuclear export.
• These findings reveal novel insights into the post-transcriptional control of muscle regeneration.