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Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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PAX7-FOXO1 Drosophila Microarray

ABSTRACT: Our goal was to identify differentially expressed genes in Drosophila muscle when misexpressing the human PAX-FKHR fusion oncoprotein. Using the GAL4-UAS expression system, PAX7-FKHR was misexpressed in differentiating muscle. After 2-3 days of expression larval animals were collected, dissected to remove as much non-muscle internal tissue as possible, mRNA extracted, and expression profiling done with Affy Drosophila 2.0 genome chips

ORGANISM(S): Drosophila melanogaster

SUBMITTER: Rene Galindo

PROVIDER: E-MTAB-839 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Drosophila and mammalian models uncover a role for the myoblast fusion gene TANC1 in rhabdomyosarcoma.

Avirneni-Vadlamudi Usha U Galindo Kathleen A KA Endicott Tiana R TR Paulson Vera V Cameron Scott S Galindo Rene L RL

The Journal of clinical investigation 20111219 1

Rhabdomyosarcoma (RMS) is a malignancy of muscle myoblasts, which fail to exit the cell cycle, resist terminal differentiation, and are blocked from fusing into syncytial skeletal muscle. In some patients, RMS is caused by a translocation that generates the fusion oncoprotein PAX-FOXO1, but the underlying RMS pathogenetic mechanisms that impede differentiation and promote neoplastic transformation remain unclear. Using a Drosophila model of PAX-FOXO1-mediated transformation, we show here that mu ...[more]

PMID: 22182840

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caArray_trich-00099: Identification of a PAX-FKHR gene expression signature that defines molecular classes and determines the prognosis of alveolar rhabdomyosarcomas

Project description:Alveolar rhabdomyosarcomas (ARMS) are aggressive soft-tissue sarcomas affecting children and young adults. Most ARMS tumors express the PAX3-FKHR or PAX7-FKHR (PAX-FKHR) fusion genes resulting from the t(2;13) or t(1;13) chromosomal translocations, respectively. However, up to 25% of ARMS tumors are fusion negative, making it unclear whether ARMS represent a single disease or multiple clinical and biological entities with a common phenotype. To test to what extent PAX-FKHR determine class and behavior of ARMS, we used oligonucleotide microarray expression profiling on 139 primary rhabdomyosarcoma tumors and an in vitro model. We found that ARMS tumors expressing either PAX-FKHR gene share a common expression profile distinct from fusion-negative ARMS and from the other rhabdomyosarcoma variants. We also observed that PAX-FKHR expression above a minimum level is necessary for the detection of this expression profile. Using an ectopic PAX3-FKHR and PAX7-FKHR expression model, we identified an expression signature regulated by PAX-FKHR that is specific to PAX-FKHR-positive ARMS tumors. Data mining for functional annotations of signature genes suggested a role for PAX-FKHR in regulating ARMS proliferation and differentiation. Cox regression modeling identified a subset of genes within the PAX-FKHR expression signature that segregated ARMS patients into three risk groups with 5-year overall survival estimates of 7%, 48%, and 93%. These prognostic classes were independent of conventional clinical risk factors. Our results show that PAX-FKHR dictate a specific expression signature that helps define the molecular phenotype of PAX-FKHR-positive ARMS tumors and, because it is linked with disease outcome in ARMS patients, determine tumor behavior. NOTE: Migrated from caArray 1.x, identifier='gov.nih.nci.ncicb.caarray:Experiment:1015897589792480:1'

2016-12-22 | GSE92689 | GEO

Divergent transcriptional and transforming properties of PAX3-FOXO1 and PAX7-FOXO1 paralogs

Project description:Hallmarks of the alveolar subclass of Rhabdomyosarcoma are chromosomal translocations that generate PAX3-FOXO1 or PAX7-FOXO1 chimeric transcription factors. Both PAX-FOXO1s drive related cell transformation in animal models, yet the two mutations are associated with distinct pathological manifestations in patients. To evaluate the mechanisms underlying these differences, we generated isogenic fibroblast lines expressing either PAX-FOXO1 paralog. Mapping their genome recruitment using CUT&Tag revealed that the two chimeric proteins have distinct DNA binding preferences. Furthermore, PAX7-FOXO1 causes stronger de novo transactivation of its bound regions than PAX3-FOXO1, resulting in greater transcriptomic dynamics involving genes regulating cell shape and cycle. Consistently, PAX3-FOXO1 accentuates fibroblast cellular traits associated with contractility and surface adhesion and limits entry to M phase. Instead, PAX7-FOXO1 pushes cells to adopt an amoeboid-like shape, reduce S phase entry and provokes more genome instabilities. Altogether, our results demonstrate that PAX7-FOXO1 has a greater chromatin remodelling and transactivating abilities and is more deleterious to cells than PAX3-FOXO1. Altogether our results argue that the diversity in rhabdomyosarcoma manifestation stems, in part, from the diverging transcriptional activity of PAX3-FOXO1 and PAX7-FOXO1. Furthermore, PAX7-FOXO1 pronounced deleterious effects provides an explanation for the low frequency of the translocation generating this factor in Rhabdomyosarcoma patients.

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Identification of Pax7 target genes in muscle stem cells

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Pax7 remodels the chromatin landscape in skeletal muscle stem cells

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2017-04-26 | GSE89977 | GEO

Gene expression response to Pax7 in murine myoblasts

Project description:Pax7 is a paired box transcription factor that is central to skeletal muscle satellite cell function Microarrays were used to examine gene expression after primary murine satellite cell-derived myoblasts were retrovirally infected with constructs encoding Pax7, PAX7-FOXO1A, dominant negative Pax7-ERD and retroviral control.

2017-02-01 | GSE77478 | GEO

Barx2 and Pax7 have antagonistic functions in regulation of Wnt signaling and satellite cell differentiation

Project description:The canonical Wnt signaling pathway is critical for myogenesis and can induce muscle progenitors to switch from proliferation to differentiation; how Wnt signals integrate with muscle specific regulatory factors in this process is poorly understood. We previously demonstrated that the Barx2 homeobox protein promotes differentiation in cooperation with the muscle regulatory factor (MRF) MyoD. Pax7, another important muscle homeobox factor represses differentiation. We now identify Barx2,MyoD,and Pax7 as novel components of the Wnt effector complex, providing a new molecular pathway for regulation of muscle progenitor differentiation. Canonical Wnt signaling induces Barx2 expression in muscle progenitors and perturbation of Barx2 leads to misregulation of Wnt target genes. Barx2 activates two endogenous Wnt target promoters as well as the Wnt reporter gene TOPflash, the latter synergistically with MyoD. Moreover, Barx2 interacts with the core Wnt effectors Î²-catenin and TCF, is recruited to TCF/LEF sites, and promotes recruitment of Î²-catenin. In contrast, Pax7 represses the Wnt reporter gene and antagonizes the activating effect of Barx2. Pax7 also binds Î²-catenin suggesting that Barx2 and Pax7 may compete for interaction with the core Wnt effector complex. Overall, the data show for the first time that Barx2, Pax7, and MRFs can act as direct transcriptional effectors of Wnt signals in myoblasts and that Barx2 and Wnt signaling participate in a regulatory loop. We propose that antagonism between Barx2 and Pax7 in regulation of Wnt signaling may help mediate the switch from myoblast proliferation to differentiation. RNA-Seq analyses was used to characterize gene expression in primary myoblasts from wild-type and Barx2 knockout mice.

2015-10-22 | E-GEOD-53398 | biostudies-arrayexpress

Human muscle-derived CLEC14A-positive cells regenerate muscle independent of PAX7

Project description:Skeletal muscle stem cells, called satellite cells, are responsible for postnatal muscle growth, homeostasis and regeneration. Attempts to utilize the regenerative potential of muscle stem cells for therapeutic purposes so far failed. The transcription factor Pax7 defines satellite cells across species 1-4 . We previously established human PAX7-positive cell colonies with high regenerative potential 5 . We now identified PAX7-negative human muscle-derived cell colonies (PAX7neg) also positive for the myogenic markers desmin and MYF5. These included cells from a unique myopathic patient with rigid spine and respiratory insufficiency due to a homozygous PAX7 c.86-1G>A mutation (PAX7null). Single cell and bulk transcriptome analysis showed high intra- and inter-donor heterogeneity and revealed the endothelial cell marker CLEC14A to be highly expressed in PAX7null cells. All PAX7neg cell populations, including PAX7null, formed myofibers after transplantation into mice, and regenerated muscle after reinjury. Transplanted PAX7neg cells repopulated the satellite cell niche where they re-expressed PAX7. Strikingly, PAX7null cells expressing CLEC14A were also identified below the basal lamina. In summary, transplanted human cells do not depend on PAX7 for muscle regeneration. Thus, Pax7 is not a suitable marker for selection of optimal cells for muscle regenerative therapies.

2019-11-11 | GSE117382 | GEO

Identification of Pax7 target genes in muscle progenitor cells from young mice

Project description:To identify Pax7 target genes in muscle progenitor cells, we compared the transcriptome profiles of muscle progenitor cells from young mice (P12) with and without Pax7.

2017-05-22 | GSE97690 | GEO

Acetylation of PAX7 Controls Muscle Stem Cell Self-Renewal and Differentiation Potential

Project description:It has been suggested that muscle stem cell function is regulated by Acetyl-CoA and NAD+ availability, but the mechanisms remain unclear. We identified two acetylation sites on PAX7 that positively regulate its transcriptional activity. Lack of PAX7 acetylation reduces DNA binding, specifically to the homeobox motif. The acetyltransferase MYST1 stimulated by Acetyl-CoA, and the deacetylase SIRT2 stimulated by NAD+, were identified as direct regulators of PAX7 acetylation and asymmetric division in muscle stem cells. Abolishing PAX7 acetylation in mice using CRISPR/Cas9 mutagenesis led to an expansion of the satellite stem cell pool, reduced numbers of asymmetric stem cell divisions, and increased numbers of oxidative IIA myofibers. Gene expression analysis confirmed that lack of PAX7 acetylation preferentially affects the expression of target genes regulated by homeodomain binding motifs. Thus, PAX7 acetylation status regulates muscle stem cell function and differentiation potential to facilitate metabolic adaptation of muscle tissue.

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Rhabdomyosarcoma can be initiated in activated Pax7+ Muscle Progenitor Cells

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2011-01-30 | E-GEOD-25098 | biostudies-arrayexpress

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