Dataset of the week — GSE70955

by Shruti Mehrotra

Our ‘Dataset of the Week’ series features publicly available omics datasets of scientific value, intending to promote data sharing and reuse.

Publication: Cell Reports, 2016.

This week, we feature a microarray gene expression profile generated on an Affymetrix PrimeView human oligonucleotide array from the publication titled ‘Concordant but Varied Phenotypes among Duchenne Muscular Dystrophy Patient-Specific Myoblasts Derived using a Human iPSC-Based Model’(1).

Clinical Problem:

Duchenne Muscular Dystrophy (DMD) is characterized by deteriorated muscle functioning caused by degeneration of myocytes (muscle cells). This genetic disorder is caused by a dysfunction of the DMD gene that regulates the production of dystrophin, contributing to the reinforcement of muscle fibers. Although previous studies have documented histological pathologies and molecular mechanisms of DMD in animal models, human cell DMD models have been rarely assessed(2,3). Researchers have used hiPSCs to demonstrate an in-vitro DMD model in humans that exhibited patient-specific dystrophin mutations.

Graphical Abstract

Experimental Design:

Human embryonic stem cells were differentiated into skeletal muscle cells and compared to non-differentiated cells in triplicates. Microarray gene expression profiles were generated for the confirmation of differentiated cell characteristics. Global mRNA profiles were used to detail the gene expression underlying cellularization and to identify up-regulated genes involved in this process. Furthermore, microarray datasets were used for comparing control and disease gene expression profiles.

Key findings of the publication:

• DMD myoblasts cultured in this experiment displayed patient-specific phenotypes — including altered transcriptional profiles, aberrant intracellular signaling, and defective myotube formation.
• Using genetic correction and pharmacological “dual-SMAD” inhibition, the DMD-hiPSC-derived myoblasts formed “rescued” myotubes.
• Affected myoblasts were observed to have increased BMP4 and TGFB signaling levels with aberrant expression of interleukins 6 and 8 and collagen 3 forming genes.
• SPP1 (Osteopontin), BMP4, CASPASE1, BMP2, and TGFβ3 were reported to be the most positively correlated genes in the case of DMD myoblasts. SPP1 has been shown to be a potent genetic modifier of disease severity in DMD in previous studies(4).

Significance of the dataset:

PCA plot depicting clusters of normal embryonic stem cells (olive) and DMD-hiPSC-derived cells (purple). The plot is generated on Polly.

Volcano plot showing the statistical significance of several genes including MYOZ1 (Myozenin 1) which is involved with muscle strength. Plot generated on Polly.

Links: Full Article | Dataset: GSE70955 | PMID | DOI | OmixWiki | Polly

References:

1. Choi IY., et al. Concordant but Varied Phenotypes among Duchenne Muscular Dystrophy Patient-Specific Myoblasts Derived using a Human iPSC-Based Model. Cell Rep vol. 15, 2301–12 (2016).
2. Barberi, T., Bradbury M., et al. Derivation of engraftable skeletal myoblasts from human embryonic stem cells. Nat. Med.1vol. 3, 642–648 (2007).
3. Li, H.L., Fujimoto, N., et al. Precise correction of the dystrophin gene in Duchenne muscular dystrophy patient induced pluripotent stem cells by TALEN and CRISPR-Cas9. Stem Cell Reports vol. 4, 143–154 (2015).
4. Pegoraro, E., Hoffman, E.P., et al. Cooperative International Neuromuscular Research Group SPP1 genotype is a determinant of disease severity in Duchenne muscular dystrophy. Neurology vol. 76, 219–226 (2011).