This study analyzed mRNA profiles in rhombomere 4 of E10.5 mouse knock-in embryos expressing either normal endogenous Hox-B1 protein or the paralogous Hox-A1 protein from the Hoxb1 locus. The Hox-A1 protein was found to be detectably less efficacious than Hox-B1 in promoting neurogenesis in the basal plate of rhombomere 4 and its transcriptional profile shared several similarities with the Hoxb1 mutant.
Reversal of Hox1 gene subfunctionalization in the mouse.
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View SamplesHoxb1 is required for proper specification of rhombomere 4 and the facial motor neurons. This study analyzed gene expression in the corresponding hindbrain segment of E10.5 mutant embryos. Several genetic pathways were found altered, including transcription factors such as Phox2b, Gata3, Nkx2-2 and Nkx6-1.
Reversal of Hox1 gene subfunctionalization in the mouse.
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View SamplesSynovial sarcoma-like tumors were generated in mice by conditionally expressing the human t(X;18) translocation-derived SYT-SSX2 fusion protein. Using a Tamoxifen-inducible CreER system, we show here that sporadic expression of SYT-SSX2 across multiple tissue types leads to exclusive formation of synovial sarcoma-like tumors while its widespread expression is lethal. CreER-based sporadic expression both avoids the severe early developmental phenotypes associated with widespread SYT-SSX2 expression and better models natural pathogenesis of cancers where transformed cells usually arise within an environment of largely normal cells.
A CreER-based random induction strategy for modeling translocation-associated sarcomas in mice.
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View SamplesThe human SYT-SSX fusion protein was expressed in a developmentally dependent fashion in murine myoblasts. Tumors harvested from mice in adolescence were compared to normal mouse skeletal muscle samples.
A conditional mouse model of synovial sarcoma: insights into a myogenic origin.
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View SamplesProfile gene expression from tumors that develop in mice bearing conditional activation of EWS-ATF1, compared to control mouse tissues from the chest wall as well as tumor samples from mouse models of synovial sarcoma and osteosarcoma achieved by conditional disruption of Rb1 and p53 Overall design: 13 clear cell sarcomas (5 started with Rosa26CreER, 4 with TATCre, 2 with Prx1CreERT2, and 2 with Bmi1IRESCreERT2), 7 osteosarcomas, 6 synovial sarcomas, 6 control samples
Modeling clear cell sarcomagenesis in the mouse: cell of origin differentiation state impacts tumor characteristics.
Specimen part, Subject
View SamplesMetabolically active cells require robust mechanisms to combat oxidative stress. The cytoplasmic thioredoxin reductase/thioredoxin (Txnrd1/Txn1) system maintains reduced protein dithiols and provides electrons to some cellular reductases, including peroxiredoxins.
Cytoprotective Nrf2 pathway is induced in chronically txnrd 1-deficient hepatocytes.
Specimen part
View SamplesHoxb8 mutant mice show compulsive behavior similar to trichotillomania, a human obsessive-compulsive-spectrum disorder. The only Hoxb8 lineage-labeled cells in the brains of mice are microglia, suggesting that defective Hoxb8 microglia caused the disorder. What is the source of the Hoxb8 microglia? It has been posited that all microglia progenitors arise at embryonic day (E) 7.5 during yolk sac hematopoiesis, and colonize the brain at E9.5. In contrast, we show the presence of two microglia subpopulations: canonical, non-Hoxb8 microglia and Hoxb8 microglia. Unlike non- Hoxb8 microglia, Hoxb8 microglia progenitors appear to be generated during the second wave of yolk sac hematopoiesis, then detected in the aorto-gonad-mesonephros (AGM) and fetal liver, where they are greatly expanded, prior to infiltrating the E12.5 brain. Further, we demonstrate that Hoxb8 hematopoietic progenitor cells taken from fetal liver are competent to give rise to microglia in vivo. Although the two microglial subpopulations are very similar molecularly, and in their response to brain injury and participation in synaptic pruning, they show distinct brain distributions which might contribute to pathological specificity. Non-Hoxb8 microglia significantly outnumber Hoxb8 microglia, but they cannot compensate for the loss of Hoxb8 function in Hoxb8 microglia, suggesting further crucial differences between the two subpopulations. Overall design: Green (non-Hoxb8, control) and yellow (Hoxb8, experimental) microglia data sets
Correction: Two distinct ontogenies confer heterogeneity to mouse brain microglia (doi: 10.1242/dev.152306).
Age, Specimen part, Cell line, Subject
View SamplesThe goal of this study was to determine the transcriptional changes associated with breast cancer cells undergoing vascular mimicry in a 3D assay. Two breast cancer cell lines were plated on matrigel in the presence or absence of serum. MDA-MB-231 cells undergo vascular mimicry on matrigel in the absence of serum, MDA-MB-453 cells do not. Overall design: Four samples were analyzed. MDA-MB-231 and MDA-MB-453 cells were plated for 24 hours on matrigel in the presence or absence of serum. MDA-MB-231 cells undergo vascular mimicry when plated on matrigel in the absence of serum, while MDA-MB-453 cells do not.
ZEB1-repressed microRNAs inhibit autocrine signaling that promotes vascular mimicry of breast cancer cells.
No sample metadata fields
View SamplesGenetic disruption of thioredoxin reductase 1 protects against acetaminophen (APAP) toxicity.
A Txnrd1-dependent metabolic switch alters hepatic lipogenesis, glycogen storage, and detoxification.
Sex, Specimen part
View SamplesGene fusions arising from chromosomal translocations are key oncogenic drivers in soft tissue sarcomas but little is known about how they exert their oncogenic effects. Our study explores the molecular mechanisms by which the SS18-SSX fusion oncoprotein subverts epigenetic mechanisms of gene regulation to drive synovial sarcoma. Using functional genomics, we identify KDM2B – a histone demethylase and core component of a non-canonical Polycomb Repressive Complex 1 (PRC1.1) – as selectively required for sustaining synovial sarcoma cell transformation. SS18-SSX physically interacts with PRC1.1 and co-associates with SWI/SNF and KDM2B complexes on unmethylated CpG islands genome-wide. Via KDM2B, SS18-SSX binds and aberrantly activates expression of a series of developmentally regulated transcription factors that would otherwise be targets of polycomb-mediated repression, which is restored upon KDM2B depletion leading to irreversible mesenchymal differentiation. Thus, SS18-SSX de-regulates developmental programs to drive transformation by hijacking a transcriptional repressive complex to aberrantly activate gene expression. Overall design: RNA-Seq of human synovial sarcoma cells (HS-SY-II) in control cells (Ren.173) and upon knockdown of SS18-SSX1 (SS18.273 and SSX.1274) or of KDM2B (KDM2B. 4395 and KDM2B.4835) in duplicates.
The SS18-SSX Oncoprotein Hijacks KDM2B-PRC1.1 to Drive Synovial Sarcoma.
Subject
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