Functions and Regulatory Mechanisms of Ribosomal Protein S27-like Gene in Skeletal Muscle development

Xiaoqin Liu

Natural and artificial selection has led to significant phenotypic differences in skeletal muscle growth between local Chinese and Western commercial pig breeds. This phenotypic differ in skeletal muscle growth may in part be characterised by differences in RNA-binding proteins (RBPs) which are crucial determinants of gene expression. However, the number of muscular associated RBPs or their genetic variants that have been identified are still limited. This thesis explores the regulation of ribosomal protein S27-like (RPS27L), an RBP that is differentially expressed between local Chinese and Western commercial pig breeds. We have used muscle-specific Rps27l knock-in mice to elucidate the function and regulatory mechanisms of this RBP. The first experiment of this thesis examined the expression patterns of RPS27L in pigs through transcriptome comparisons. Whole genome sequencing was used to identify variants in or around the genic region of RPS27L. A 13-bp insertion-deletion (InDel) was identified within the RPS27L promoter. The insertion is nearly fixed in Chinese local pig breeds, while the deletion is prevalent in most Western commercial pig breeds. The luciferase reporter assays demonstrated that the transcriptional activity of RPS27L in Chinese local pigs is regulated by transcription factor 3 (TCF3) and myogenic differentiation antigen (MYOD) within the 13-bp insertion region. Furthermore, association studies demonstrated this InDel was associated with the body weight of pigs. The second experiment investigated the regulatory mechanism of Rps27l in the skeletal muscle of mice. Muscle-specific Rps27l knock-in (M-KI) mice exhibited elevated muscle mass, larger myofiber size and displayed increased proportions of fast-twitch myofibers and enhanced muscle regeneration capability. We demonstrated that Rps27l controlled these myogenic responses through the SIX4/Rps27l/IGF1 axis. Notably, Rps27l protein translocation drives liquid liquid phase separation (LLPS) via its N-terminal intrinsically disordered region, where it interacts with target IGF1 to co-regulate myogenesis. The M-KI mice have therefore shed light on the novel regulatory mechanism of RPS27L-driven LLPS in myogenesis. In conclusion, our results demonstrate the role of RPS27L in skeletal muscle development and growth in pigs and mice, suggesting that RPS27L is a potential myogenetic marker.

Functions and Regulatory Mechanisms of Ribosomal Protein S27-like Gene in Skeletal Muscle development

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