Opposing gene regulatory programs governing myofiber development and maturation revealed at single nucleus resolution

Area of Science:

• Developmental Biology
• Molecular Biology
• Genetics

Background:

• Skeletal muscle fibers exhibit distinct gene programs during development and maturation.
• The gene regulatory networks controlling stage-specific myofiber properties are not fully understood.
• Understanding these networks is crucial for deciphering muscle development and response to neural activity.

Purpose of the Study:

• To generate a multi-omic atlas of mouse skeletal muscle development.
• To identify gene regulatory networks controlling muscle fiber development and maturation.
• To investigate the role of neural activity in these processes.

Main Methods:

• Combined multi-omic single-nucleus RNA-sequencing (snRNA-seq) and ATAC-sequencing (ATAC-seq).
• Analysis of mouse skeletal muscle at multiple embryonic, fetal, and postnatal stages.
• Identification of key transcription factors and their regulatory roles.

Main Results:

• Myogenin, Klf5, and Tead4 form a complex that activates muscle gene expression in developing myofibers.
• The transcription factor Maf acts as a switch for mature fast muscle gene program activation during maturation.
• Impaired Maf expression and myofiber maturation were observed in mice lacking voltage-gated L-type Ca2+ channels (Cav1.1).

Conclusions:

• This study provides a comprehensive transcriptional atlas of skeletal muscle development.
• Key transcription factors and their networks governing myofiber formation and maturation were identified.
• Genetic links between myofiber development, maturation, and muscle contraction are revealed.