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Gene expression profiling induced by overexpression and silencing of Ankrd2

ABSTRACT: We have used a genomic approach based on microarray technology in order to identify the gene networks that are disturbed by Ankrd2 overexpression and silencing. We performed the experiments at the myoblast stage, because there Ankrd2 localizes in the nucleus where it may act as myogenic transcriptional regulator. The stable alteration of Ankrd2 expression level resulted in the modulation of different muscle differentiation-related genes belonging to functional classes having key roles in myogenesis (cell cycle regulation and apoptosis; skeletal muscle development and contraction; cell adhesion and cytoskeletal organization). The transcriptional profile of Ankrd2-overexpressing clones highlights a remarkable impairment of the myogenic differentiation program. In the same clones the alteration of genes regulating cell cycle and apoptosis shows that the Ankrd2 overexpression leads to raised C2C12 proliferation compromising the response to serum deprivation and then myotube formation. On the other side, in Ankrd2-silenced clones numerous genes promoting cell cycle arrest are found upregulated. Keywords: gene-specific overexpression and silencing

ORGANISM(S): Mus musculus

PROVIDER: GSE7542 | GEO | 2008/12/09

SECONDARY ACCESSION(S): PRJNA99373

REPOSITORIES: GEO

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Project description:ABSTRACT Stimulating the commitment of implanted dystrophin+ muscle derived stem cells (MDSC) into myogenic, as opposed to lipofibrogenic, lineages is a promising therapeutic strategy for Duchenne muscular dystrophy (DMD). To examine whether counteracting myostatin, a negative regulator of muscle mass and a pro-lipofibrotic factor, would help this process, we compared the in vitro myogenic and fibrogenic capacity of MDSC from wild type (WT), myostatin knockout (Mst KO), and mdx (DMD model) (mdx) young mice under various modulators, the expression of key stem cell and myogenic genes, and the capacity of these MDSC to repair the injured gastrocnemius in aged mdx mice with exacerbated lipofibrosis. Surprisingly, the potent in vitro myotube formation by WT MDSC was refractory to modulators of myostatin expression or activity, and the Mst KO and mdx MDSC failed to form myotubes under any condition, despite all MDSC expressed Oct-4 and various stem cell genes and differentiated into other lineages. The genetic inactivation of myostatin or dystrophin in MDSC was associated with silencing of critical genes for early myogenesis (Actc1, Acta1, and MyoD). WT MDSC implanted into the injured gastrocnemius of old mdx mice significantly improved myofiber repair and reduced fat deposition and, to a lesser extent, fibrosis. In contrast to their in vitro behavior, Mst KO MDSC in vivo also significantly improved myofiber repair, but had no significant effects on lipofibrotic degeneration. In conclusion, while WT MDSC are considerably myogenic in culture and stimulate muscle repair after injury in the aged mdx mouse, myostatin genetic inactivation blocks myotube formation in vitro but the myogenic capacity is recovered in vivo under the influence of the host tissue environment, presumably by reactivation of key genes originally silenced in the Mst KO MDSC. Key words: dystrophin, mdx mouse, Duchenne, fibrosis, dystrophy One sample each of mouse wild type (WT), myostatin knockout (KO), muscular dystrophy model mdx, and the transgenic OCT4 promoter plus reporter were grown, RNA was isolated, and subjected to the SABiosciences mouse stem cell oligo array.

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Gene expression profiling induced by overexpression and silencing of Ankrd2

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