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Gene expression during normal and FSHD myogenesis.

Publication ,  Journal Article
Tsumagari, K; Chang, S-C; Lacey, M; Baribault, C; Chittur, SV; Sowden, J; Tawil, R; Crawford, GE; Ehrlich, M
Published in: BMC Med Genomics
September 27, 2011

BACKGROUND: Facioscapulohumeral muscular dystrophy (FSHD) is a dominant disease linked to contraction of an array of tandem 3.3-kb repeats (D4Z4) at 4q35. Within each repeat unit is a gene, DUX4, that can encode a protein containing two homeodomains. A DUX4 transcript derived from the last repeat unit in a contracted array is associated with pathogenesis but it is unclear how. METHODS: Using exon-based microarrays, the expression profiles of myogenic precursor cells were determined. Both undifferentiated myoblasts and myoblasts differentiated to myotubes derived from FSHD patients and controls were studied after immunocytochemical verification of the quality of the cultures. To further our understanding of FSHD and normal myogenesis, the expression profiles obtained were compared to those of 19 non-muscle cell types analyzed by identical methods. RESULTS: Many of the ~17,000 examined genes were differentially expressed (>2-fold, p<0.01) in control myoblasts or myotubes vs. non-muscle cells (2185 and 3006, respectively) or in FSHD vs. control myoblasts or myotubes (295 and 797, respectively). Surprisingly, despite the morphologically normal differentiation of FSHD myoblasts to myotubes, most of the disease-related dysregulation was seen as dampening of normal myogenesis-specific expression changes, including in genes for muscle structure, mitochondrial function, stress responses, and signal transduction. Other classes of genes, including those encoding extracellular matrix or pro-inflammatory proteins, were upregulated in FSHD myogenic cells independent of an inverse myogenesis association. Importantly, the disease-linked DUX4 RNA isoform was detected by RT-PCR in FSHD myoblast and myotube preparations only at extremely low levels. Unique insights into myogenesis-specific gene expression were also obtained. For example, all four Argonaute genes involved in RNA-silencing were significantly upregulated during normal (but not FSHD) myogenesis relative to non-muscle cell types. CONCLUSIONS: DUX4's pathogenic effect in FSHD may occur transiently at or before the stage of myoblast formation to establish a cascade of gene dysregulation. This contrasts with the current emphasis on toxic effects of experimentally upregulated DUX4 expression at the myoblast or myotube stages. Our model could explain why DUX4's inappropriate expression was barely detectable in myoblasts and myotubes but nonetheless linked to FSHD.

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Published In

BMC Med Genomics

DOI

EISSN

1755-8794

Publication Date

September 27, 2011

Volume

4

Start / End Page

67

Location

England

Related Subject Headings

  • Up-Regulation
  • Reverse Transcriptase Polymerase Chain Reaction
  • RNA Isoforms
  • Oligonucleotide Array Sequence Analysis
  • Myoblasts
  • Muscular Dystrophy, Facioscapulohumeral
  • Muscle Fibers, Skeletal
  • Muscle Development
  • Humans
  • Homeodomain Proteins
 

Citation

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Tsumagari, K., Chang, S.-C., Lacey, M., Baribault, C., Chittur, S. V., Sowden, J., … Ehrlich, M. (2011). Gene expression during normal and FSHD myogenesis. BMC Med Genomics, 4, 67. https://doi.org/10.1186/1755-8794-4-67
Tsumagari, Koji, Shao-Chi Chang, Michelle Lacey, Carl Baribault, Sridar V. Chittur, Janet Sowden, Rabi Tawil, Gregory E. Crawford, and Melanie Ehrlich. “Gene expression during normal and FSHD myogenesis.BMC Med Genomics 4 (September 27, 2011): 67. https://doi.org/10.1186/1755-8794-4-67.
Tsumagari K, Chang S-C, Lacey M, Baribault C, Chittur SV, Sowden J, et al. Gene expression during normal and FSHD myogenesis. BMC Med Genomics. 2011 Sep 27;4:67.
Tsumagari, Koji, et al. “Gene expression during normal and FSHD myogenesis.BMC Med Genomics, vol. 4, Sept. 2011, p. 67. Pubmed, doi:10.1186/1755-8794-4-67.
Tsumagari K, Chang S-C, Lacey M, Baribault C, Chittur SV, Sowden J, Tawil R, Crawford GE, Ehrlich M. Gene expression during normal and FSHD myogenesis. BMC Med Genomics. 2011 Sep 27;4:67.
Journal cover image

Published In

BMC Med Genomics

DOI

EISSN

1755-8794

Publication Date

September 27, 2011

Volume

4

Start / End Page

67

Location

England

Related Subject Headings

  • Up-Regulation
  • Reverse Transcriptase Polymerase Chain Reaction
  • RNA Isoforms
  • Oligonucleotide Array Sequence Analysis
  • Myoblasts
  • Muscular Dystrophy, Facioscapulohumeral
  • Muscle Fibers, Skeletal
  • Muscle Development
  • Humans
  • Homeodomain Proteins