Exon skipping in genes encoding lineage-defining myogenic transcription factors in rhabdomyosarcoma

Rhabdomyocarcoma (RMS) contains myoblast-like cells that fail in terminal differentiation. To explore the potential defects in differentiation, we studied mRNA splicing variants in genes encoding transcription factors critical for skeletal muscle differentiation with RNA-Seq data from RMS specimens and cell lines. We identified novel exon 2 skipping form of MYOD1 and MYF5. Further study on MYOD?Ex2 protein showed that it failed to robustly induce muscle-specific genes but its ectopic expression conferred a selective advantage in cultured fibroblasts and an RMS xenograft. Therefore, alternative splicing can represent a mechanism to alter the function of these two transcription factors in RMS. Overall design: Bulk RNA-Seq was carried out with 6 RMS cell lines and human skeletal muscle myoblasts (HSMM).