RNA-Binding Proteins Direct Myogenic Cell Fate Decisions

Abstract

RNA-binding proteins (RBPs) are essential for skeletal muscle regeneration and RBP dysfunction causes muscle degeneration and neuromuscular disease. How ubiquitously expressed RBPs orchestrate complex tissue regeneration and direct cell fate decisions in skeletal muscle remains poorly understood. Single cell RNA-sequencing of regenerating skeletal muscle reveals that RBP expression, including numerous neuromuscular disease-associated RBPs, is temporally regulated in skeletal muscle stem cells and correlates to stages of myogenic differentiation. By combining machine learning with RBP engagement scoring, we discover that the neuromuscular disease associated RBP Hnrnpa2b1 is a differentiation-specifying regulator of myogenesis controlling myogenic cell fate transitions during terminal differentiation. The timing of RBP expression specifies cell fate transitions by providing a layer of post-transcriptional regulation needed to coordinate stem cell fate decisions during complex tissue regeneration.

Macrophage inflammatory and regenerative response periodicity is programmed by cell cycle and chromatin state

“…Next, we analyzed another muscle regeneration dataset, in which regeneration was studied after barium chloride-induced tibialis anterior injury at days 4 and 7 after the challenge [48]. We subset MFs by the expression of Mrc1 , Msr1 , Itgam and Adgre1 (LogNorm.Expression>0.5), performed dimensionality reduction and identified 5 clusters (Figure S7E and S7F) .…”

“…Therefore, we propose that CC entry might provide a cyclical mechanism to dampen inflammation and support regeneration. Using published scRNA-seq datasets of regenerating muscle, we identified proliferating MF subsets, where the expression of tissue remodeling genes ( Col1a1 and Col1a2 ) and CC genes displayed positive correlation at the single cell level [47, 48]. Furthermore, spatial transcriptomics of wound healing also supported this concept, by defining a tissue layer of high MF-specific gene expression, along with the expression of the tissue remodeling gene set and Mki67 [49].…”

Notch signaling determines cell-fate specification of the two main types of vomeronasal neurons of rodents

“…5). As RBPs can also control cell fate choice by post-transcriptionally modulating mRNA and miRNA dynamics [74][75][76], it would be interesting to further study whether…”

Expanding the TDP-43 Proteinopathy Pathway From Neurons to Muscle: Physiological and Pathophysiological Functions

“…The role of different RNA-binding proteins in myogenesis is reported in the literature, including the role of TDP-43. TDP-43 is mainly present in the earlier stages of myogenesis, and the TDP-43 levels are found to be at their highest in Pax7positive MuSCs and in regenerating myofibers 5 days after injury (Wheeler et al, 2021). During muscle regeneration TDP-43 relocalizes to the cytoplasm and exists as a component of amyloidlike myo-granules.…”

“…Skeletal muscles are required for movement and for the body's structural integrity, but also have important endocrine and metabolic functions (Yin et al, 2013;Fealy et al, 2021). The muscle tissue is composed of myofibers which contain the functional units, known as sarcomeres, and houses muscle stem cells (MuSCs) (Yin et al, 2013;Wheeler et al, 2021). The MuSCs typically reside in a quiescent state but become activated after damage.…”