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CHAMP1 is an essential regulator for human myoblast fusion and muscle development

ABSTRACT: Human skeletal muscle is composed of myofibers, each formed by the fusion of thousands of individual myoblasts. This process requires tightly regulated expression of muscle-specific fusogens, which confer both efficiency and muscle specificity to cell-cell fusion. Currently, the genetic regulation of this process remains poorly understood. Here, we identify CHAMP1, a chromosome alignment factor, as a surprising upstream activator of human myoblast fusion. Genetic deletion of CHAMP1 in human myoblasts led to profound fusion defects in vitro and in vivo following transplantation. Leveraging genomics approach and protein interaction assays, we uncovered a noncanonical role for CHAMP1 as a transcriptional cofactor for MyoD, directly activating the expression of the key muscle fusogen Myomaker. CHAMP1 mutations in human patients cause developmental delay, hypotonia, and muscle weakness, hallmarks of fusion myopathy that are also observed with Myomaker mutations. Importantly, CHAMP1 patient-derived cells exhibit severe fusion defects that can be fully rescued by restoring Myomaker expression. Structure and function analysis identified C2H2-type zinc finger motifs on CHAMP1 protein that are both necessary and sufficient for interaction with MyoD, activation of Myomaker transcription and human myoblast fusion. These findings highlight the muscle-autonomous role of CHAMP1 in muscle development and disease, and point to therapeutic avenues for treating muscle development defect caused by CHAMP1 mutations.

ORGANISM(S): Homo sapiens

PROVIDER: GSE307319 | GEO | 2025/10/24

REPOSITORIES: GEO

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Project description:Epigenetic changes are implicated in repair and physiological responses of postnatal skeletal muscle (SkM) as well as in prenatal embryogenesis. This study examined the epigenomics and transcriptomics of human myoblasts (SkM progenitor cells) vs. those of diverse other cell and tissue types from both global genomic and single-gene perspectives. Using enzymatic methyl-seq (EM-seq) and whole-genome bisulfite sequencing (WGBS) of myoblast DNA and available WGBS profiles of other cell cultures, we determined myoblast differentially methylated regions (DMRs). We also examined several DMRs in reporter gene assays. Among the unusual findings was the positive association of promoter-adjacent hypermethylation in myoblasts with transcription turn-on for some genes (e.g., SIM2 and TWIST1), but at down-modulated levels. In contrast, some genes, like the brain-specific OLIG2, were silent and embedded in repressed chromatin in myoblasts and many diverse cell populations but displayed myoblast-specific hypermethylated promoters. OLIG2 exhibited binding of the myogenic MYOD transcription factor in its vicinity. One OLIG2-downstream MYOD+ site overlapped enhancer chromatin in myotubes. These findings suggest that OLIG2 silencing only by repressive chromatin is insufficient in myoblasts without the addition of DNA hypermethylation. The numerous hypomethylated DMRs at enhancer chromatin in myoblasts were bound by MYOD much more frequently than by CTCF. Combined with previous studies, our results suggest a more prevalent role for MYOD than for CTCF in organizing transcription-enhancing chromatin interactions at hypomethylated regions. We also found that myoblast-hypomethylated enhancer chromatin enriched in H3K36me3 was much more likely to be associated with genes preferentially expressed in myoblasts than were such regions without H3K36me3 enrichment. Therefore, there may be a special role in gene upregulation for the regional combination of DNA hypomethylation with H3K27ac, H3K4me1, and H3K36me3 enrichment. The unusual relationships between epigenetics and gene expression that we observed need further study in the SkM lineage to better understand fine-tuning of muscle differentiation and diseases.

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CHAMP1 is an essential regulator for human myoblast fusion and muscle development

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