Department of Biochemistry, University of Colorado, Boulder, United States; Medical Scientist Training Program, University of Colorado Anschutz Medical Campus, Aurora, United States; Howard Hughes Medical Institute, University of Colorado, Boulder, United States; Department of Pathology, Stanford University, Stanford, United States; Department of Neuropathology, Stanford University, Stanford, United States
Medical Scientist Training Program, University of Colorado Anschutz Medical Campus, Aurora, United States; Department of Molecular, Cellular and Developmental Biology, University of Colorado, Boulder, United States; Department of Surgery, University of Colorado, Aurora, United States
Eric D Nguyen
Medical Scientist Training Program, University of Colorado Anschutz Medical Campus, Aurora, United States; Molecular Biology Program and Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, United States
Bradley Pawlikowski
Department of Molecular, Cellular and Developmental Biology, University of Colorado, Boulder, United States
Evan Lester
Department of Biochemistry, University of Colorado, Boulder, United States; Medical Scientist Training Program, University of Colorado Anschutz Medical Campus, Aurora, United States
Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, United States; Paul F. Glenn Center for the Biology of Aging, Stanford University School of Medicine, Stanford, United States; Center for Tissue Regeneration, Repair, and Restoration, Veterans Affairs Palo Alto Health Care System, Palo Alto, United States
Center for Personal and Dynamic Regulomes, Stanford University, Palo Alto, United States; Howard Hughes Medical Institute, Stanford University, Stanford, United States
Molecular Biology Program and Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, United States; University of Colorado School of Medicine, RNA Bioscience Initiative, University of Colorado Anschutz Medical Campus, Aurora, United States
RNA-binding proteins (RBPs), essential for skeletal muscle regeneration, cause muscle degeneration and neuromuscular disease when mutated. Why mutations in these ubiquitously expressed RBPs orchestrate complex tissue regeneration and direct cell fate decisions in skeletal muscle remains poorly understood. Single-cell RNA-sequencing of regenerating Mus musculus skeletal muscle reveals that RBP expression, including the expression of many neuromuscular disease-associated RBPs, is temporally regulated in skeletal muscle stem cells and correlates with specific stages of myogenic differentiation. By combining machine learning with RBP engagement scoring, we discovered that the neuromuscular disease-associated RBP Hnrnpa2b1 is a differentiation-specifying regulator of myogenesis that controls myogenic cell fate transitions during terminal differentiation in mice. The timing of RBP expression specifies cell fate transitions by providing post-transcriptional regulation of messenger RNAs that coordinate stem cell fate decisions during tissue regeneration.
