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Inactivation of the SRF cofactors Mrtfa and Mrtfb in MEFs results in proliferation defects and reduced expression of cytoskeletal and cell cycle progression genes

ABSTRACT: The MRTFs (Myocardin-related transcription factors) are cofactors of the SRF transcription factor, and together they control dozens of growth factor-responsive, cytoskeletal and muscle specific genes. We used a conditional knockout strategy to demonstrate that in fibroblasts, inactivation of both Mrtfa and Mrtfb, or Srf, induces a severe defect in proliferation. This state exhibits features of both quiescence and senescence, with MRTF-null cells upregulating similar cell cycle regulators to serum-deprived wildtype cells, but is fully reversible by MRTF re-expression. We analysed gene expression in three MEF pools derived from Wildtype (Rosa26Tam-Cre) animals, and three MEF pools derived from Mrtfa-/-;Mrtfbfl/fl;Rosa26Tam-Cre mice. RNA was collected 0, 2, 4 or 12 days after 4-hydroxytamoxifen treatment, which inactivate Mrtfb in Mrtfa-/-;Mrtfbfl/fl;Rosa26Tam-Cre and generate MRTF-null cells. The data indicate that substantial numbers of genes exhibit altered expression in Mrtfa-/-;Mrtfb-/- cells, the difference being most pronouced 12 days following 4-OHT treatment. Genes downregulated at this point include many genes identified as serum-inducible MRTF-SRF target cells in NIH3T3 cells (Esnault et al, 2014, DOI: 10.1101/gad.239327.114) or as derepressed in MEFs following inactivation of all members of the TCF family of SRF cofactors (Gualdrini et al, 2016, DOI: 10.1016/j.molcel.2016.10.016). They are most enriched in GO categories related to actin cytoskeletal dynamics and cell signalling, and GSEA hallmarks connected with cell growth, division, and cell cycle.

ORGANISM(S): Mus musculus

PROVIDER: GSE298922 | GEO | 2025/06/05

REPOSITORIES: GEO

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Project description:Duchenne muscular dystrophy (DMD) is characterized by impaired cytoskeleton organization, cytosolic calcium handling oxidative stress and mitochondrial dysfunction. This results in progressive and fatal muscle damage, wasting and weakness. The Striated Muscle activator of Rho signalling (STARS) is an actin binding protein that activates the myocardin-related transcription factor-A (MRTFA)/serum response factor (SRF) transcriptional pathway; a pathway that regulates cytoskeletal structure, muscle function, growth and repair. Here we investigated the regulation of several members of the STARS signalling pathway in muscle from patients with DMD and the dystrophin-deficient mdx and dko (utrophin‐ and dystrophin‐null) mice. A reduction in protein levels of STARS, SRF and RHOA, and an increase in MRTFA were observed in quadriceps muscle of patients with DMD. STARS, SRF and MRTFA mRNA levels were also decreased in DMD muscle, while Stars mRNA levels were decreased in mdx tibialis anterior (TA) muscle and Srf and Mrtfa mRNAs were decreased in dko TA muscle. Overexpressing the human STARS (hSTARS) protein in mdx TA muscle increased maximal isometric specific force by 13%. This was not associated with changes in muscle mass, fibre cross-sectional area (CSA), fibre type, centralized nuclei or collagen deposition. Proteomics screening identified 31 upregulated and 22 downregulated proteins or individual peptides that were significantly regulated by hSTARS overexpression. Pathway enrichment analysis indicated that hSTARS overexpression regulated the keratin, NRF2 and oxidative phosphorylation (OXPHOS) pathways. These pathways are impaired in dystrophic muscle and regulate cytoskeleton organization, oxidative stress and mitochondrial energy production; processes that are vital for muscle function. We conclude that increasing the STARS protein in dystrophic muscle improves muscle force production, potentially via its regulation of multiple pathways that positively influence cytoskeletal structure, oxidative stress and energy production.

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Inactivation of the SRF cofactors Mrtfa and Mrtfb in MEFs results in proliferation defects and reduced expression of cytoskeletal and cell cycle progression genes

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