Finding Genes in the C2C12 Osteogenic Pathway by k-Nearest-Neighbor Classification of Expression Data

Theilhaber, Joachim; Connolly, Timothy M.; Roman-Roman, Sergio; Bushnell, Steven; Jackson, Amanda; Call, Kathy; García, Teresa; Baron, Roland

doi:10.1101/gr.182601

Cited by 65 publications

(38 citation statements)

References 46 publications

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“…Total RNA was also extracted from ST-2 and C3H10T1/2 cells under similar conditions. Total RNA samples from C2C12 cells were hybridized to the complete series of Affymetrix 35,000 mouse chips as described by Theilhaber et al (23), and data assembly and analysis were carried as described by the authors (23).…”

Section: Methodsmentioning

confidence: 99%

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Murine Frizzled-1 Behaves as an Antagonist of the Canonical Wnt/β-Catenin Signaling

Roman-Roman¹,

Shi

Stiot³

et al. 2004

Journal of Biological Chemistry

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Activation of the Wnt signaling cascade provides key signals during development and in disease. Wnt signals are transduced by seven-transmembrane Frizzleds (Fzs) and the single transmembrane low density lipoprotein receptor-related proteins 5 or 6. In the course of the analysis of genes regulated by bone morphogenetic protein 2 in mesenchymal cells we found a significant induction of murine Frizzled-1 (mFz1) gene expression. Unexpectedly overexpression of mFz1 dramatically repressed the induction of alkaline phosphatase mediated by either bone morphogenetic protein 2 or Wnt3a in these cells. Moreover mFz1 overexpression significantly repressed both ␤-catenin translocation into the nucleus and T cell factor signaling mediated by Wnt3a. Importantly microinjection of mFz1 transcript in Xenopus embryo inhibited the ability of Wnt1 to induce the expression of the Wnt/␤-catenin target gene Siamois in animal cap assay and secondary axis formation in whole embryo. By using chimeric constructs in which N-and Cterminal segments of mFz1 were replaced by the corresponding parts of Xfz3 we demonstrated that the antagonistic activity resides in the cysteine-rich domain of the N-terminal part. The antagonist activity of mFz1 could be prevented by overexpression of G␣ q -(305-359), which specifically uncouples G q -coupled receptors, suggesting that G␣ q signaling contributes to the inhibition of Wnt/␤-catenin pathway by mFz1. This is the first time that a Frizzled receptor has been reported to antagonize Wnt/␤-catenin. The transforming growth factor (TGF)1 -␤ family plays a central role in regulating a broad range of cellular responses including cell growth and differentiation. Among members of this family, bone morphogenetic proteins (BMPs) have been shown to regulate growth and differentiation of chondroblast and osteoblast lineage cells and induce the commitment of mesenchymal cells into osteoblast/chondroblast phenotypes (1-3). In addition, when ectopically implanted, BMPs possess the capacity to induce bone and cartilage formation (4, 5). In a series of murine cell lines including C3H10T1/2, C2C12, and ST2, BMP-2 induces the expression of several osteoblast differentiation markers including alkaline phosphatase (ALP) and osteocalcin (6). In contrast, TGF-␤1 has been shown to repress the expression of osteoblast markers, and it abolishes the increase in osteocalcin induced by calcitriol (7, 8). Moreover we have previously showed that TGF-␤1 is able to antagonize BMP-2 activities in several mesenchymal cell lines (9).Wnts are secreted proteins involved in a wide range of developmental processes such as embryonic axis specification and organogenesis (10). They have been shown to activate distinct pathways both in vertebrates and in invertebrates. The better described pathway is the Wnt/␤-catenin pathway. In this pathway, the interaction between Wnt and Frizzled receptors leads to inactivation of glycogen synthase kinase-3␤. Genetic epistasis experiments suggest that Dishevelled lies upstream and represses the activity of gly...

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Section: Methodsmentioning

confidence: 99%

“…genome-wide expression analysis by determining changes in expression levels of 27,000 genes with Affymetrix oligonucleotide chips (23). Among these genes Frizzled-1 (mFz1) was found to be significantly increased in the presence of BMP-2 (Fig.…”

Section: Fig 2 Frizzled-1 Inhibits Bmp-2 and Wnt Activitiesmentioning

confidence: 99%

Murine Frizzled-1 Behaves as an Antagonist of the Canonical Wnt/β-Catenin Signaling

Roman-Roman¹,

Shi

Stiot³

et al. 2004

Journal of Biological Chemistry

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“…Missing values were imputed using the inbuilt KNN algorithm of TMev 4.0 with default settings (Theilhaber et al, 2002). If two observations are described in the text as different, this means that their difference was determined to be statistically different (p £ 0.05) by the performance of the students t-test using the algorithm embedded into Microsoft Excel, differences at the p £ 0.01 level are additionally demarcated within the Supplementary data set (Microsoft, Seattle, WA).…”

Section: Discussionmentioning

confidence: 99%

Metabolite analysis for the comparison of irrigated and non-irrigated field grown tomato of varying genotype

et al. 2007

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Every year the consequences of water deficit on crop yield and quality are profound. The observation that many wild species relatives of cultivated crops display a greater stress tolerance and the fact that the cultivated species generally display only a fraction of the allelic diversity available within the tomato clade suggest that crossing of wild species with elite cultivars could improve the stress physiology of modern crops. To assess this from the basis of chemical composition we applied an established GC-MS based metabolite profiling method to fruits from irrigated and non-irrigated tomato plants either of the cultivated tomato (Solanum lycopersicum) or of its hybrid with its wild species relative (Solanum pennellii). Results are discussed in terms of both the metabolic response to drought stress and the potential of utilizing exotic germplasm as a means to improve agronomically important characteristics of crop species.

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“…In this work, the KNN method was used to classify "test subjects" generated by the HOCV procedure (see below) for internally validating the aging signature (54). An unclassified subject was classified by polling the classes (young or older) of the KNN (where a "neighbor" is a subject) in expression space, with parameter k ϭ 3 subjects, and assigning membership of that subject (young or older) based on the most prevalent class of its three neighbors.…”

Section: Knn Classificationmentioning

confidence: 99%

Identification of a molecular signature of sarcopenia

Giresi

Stevenson

Theilhaber³

et al. 2005

Physiological Genomics

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152

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Investigating the molecular mechanisms underlying sarcopenia in humans with the use of microarrays has been complicated by low sample size and the variability inherent in human gene expression profiles. We have conducted a study using Affymetrix GeneChips to identify a molecular signature of aged skeletal muscle. The molecular signature was defined as the set of expressed genes that best distinguished the vastus lateralis muscle of young ( n = 10) and older ( n = 12) male subjects, when a k-nearest neighbor supervised classification method was used in conjunction with a signal-to-noise ratio gene selection method and a holdout cross-validation procedure. The age-specific expression signature was comprised of 45 genes; 27 were upregulated and 18 were downregulated. This signature also correctly classified 75% of the muscle samples from young and older subjects published by an independent laboratory, based on their expression profiles. The signature revealed increased expression of several genes involved in mediating cellular responses to inflammation and apoptosis, including complement component C1QA, Galectin-1, C/EBP-β, and FOXO3A, among others. The increased expressions of genes that regulate pre-mRNA splicing, localization, and modification of RNA comprise markers of the aging signature. Downregulated genes in the signature were the glutamine transporter SLC38A1, a TRAF-6 inhibitory zinc finger protein, and membrane-bound transcription factor protease S2P, among others. The sarcopenia signature developed here will be useful as a molecular model to judge the effectiveness of exercise and other therapeutic treatments aimed at ameliorating the effects of muscle loss associated with aging.

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Finding Genes in the C2C12 Osteogenic Pathway by k-Nearest-Neighbor Classification of Expression Data

Cited by 65 publications

References 46 publications

Murine Frizzled-1 Behaves as an Antagonist of the Canonical Wnt/β-Catenin Signaling

Murine Frizzled-1 Behaves as an Antagonist of the Canonical Wnt/β-Catenin Signaling

Metabolite analysis for the comparison of irrigated and non-irrigated field grown tomato of varying genotype

Identification of a molecular signature of sarcopenia

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