Filters
Technology
Platform
SRP055411
Homo sapiens
11 Downloadable Samples
IlluminaHiSeq2000
Description
c-MYC (MYC) overexpression or hyperactivation is one of the most common drivers of human cancer. Despite intensive study, the MYC oncogene remains recalcitrant to therapeutic inhibition. Like other classic oncogenes, hyperactivation of MYC leads to collateral stresses onto cancer cells, suggesting that tumors harbor unique vulnerabilities arising from oncogenic activation of MYC. Herein, we discover the spliceosome as a new target of oncogenic stress in MYC-driven cancers. We identify BUD31 as a MYC-synthetic lethal gene, and demonstrate that BUD31 is a splicing factor required for the assembly and catalytic activity of the spliceosome. Core spliceosomal factors (SF3B1, U2AF1, and others) associate with BUD31 and are also required to tolerate oncogenic MYC. Notably, MYC hyperactivation induces an increase in total pre-mRNA synthesis, suggesting an increased burden on the core spliceosome to process pre-mRNA. In contrast to normal cells, partial inhibition of the spliceosome in MYC-hyperactivated cells leads to global intron retention, widespread defects in pre-mRNA maturation, and deregulation of many essential cell processes. Importantly, genetic or pharmacologic inhibition of the spliceosome in vivo impairs survival, tumorigenicity, and metastatic proclivity of MYC-dependent breast cancers. Collectively, these data suggest that oncogenic MYC confers a collateral stress on splicing and that components of the spliceosome may be therapeutic entry points for aggressive MYC-driven cancers. Overall design: Examination of intron rentention in MYC-ER HMECs, in 4 conditions
Publication Title
The spliceosome is a therapeutic vulnerability in MYC-driven cancer.
Sample Metadata Fields
No sample metadata fields
View Samples- Homo sapiens
- 28 Downloadable Samples
Affymetrix Human Gene 1.0 ST Array (hugene10st)
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
MYC-driven accumulation of 2-hydroxyglutarate is associated with breast cancer prognosis.
Sample Metadata Fields
Age, Specimen part, Disease stage, Race
View Samples- Homo sapiens
- 28 Downloadable Samples
- Affymetrix Human Gene 1.0 ST Array (hugene10st)
Description
This study identified DNA methylation patterns that were associated with tumor subtypes, disease outcome, and distinct metabolome and gene expression patterns.
Publication Title
MYC-driven accumulation of 2-hydroxyglutarate is associated with breast cancer prognosis.
Sample Metadata Fields
Age, Specimen part, Disease stage, Race
View Samples- Mus musculus
- 18 Downloadable Samples
- Illumina HiSeq 2500
Description
Gprc6a|Mck-/- (Gcrp6a skeletal muscle specific knockout)(n=4) are compared to Gprc6afl/fl (WT) mice (n=4). Gprc6a is the osteocalcin receptor. Overall design: Gprc6a/Mck-/- vs Gprc6afl/fl
Publication Title
Osteocalcin Signaling in Myofibers Is Necessary and Sufficient for Optimum Adaptation to Exercise.
Sample Metadata Fields
Specimen part, Subject
View Samples- Mus musculus
- 6 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
SIRT6 is a member of a highly conserved family of NAD+-dependent deacetylases with various roles in metabolism, stress resistance, and life span. SIRT6- deficient mice develop normally but succumb to a lethal hypoglycemia early in life; however, the mechanism underlying this hypoglycemia remained unclear. Here, we demonstrate that SIRT6 functions as a histone H3K9 deacetylase to control the expres- sion of multiple glycolytic genes. Specifically, SIRT6 appears to function as a corepressor of the transcrip- tion factor Hif1a, a critical regulator of nutrient stress responses. Consistent with this notion, SIRT6-defi- cient cells exhibit increased Hif1a activity and show increased glucose uptake with upregulation of glycolysis and diminished mitochondrial respiration. Our studies uncover a role for the chromatin factor SIRT6 as a master regulator of glucose homeostasis and may provide the basis for novel therapeutic approaches against metabolic diseases, such as diabetes and obesity.
Publication Title
The histone deacetylase Sirt6 regulates glucose homeostasis via Hif1alpha.
Sample Metadata Fields
Specimen part
View Samples- Homo sapiens
- 4 Downloadable Samples
Description
How genomic information is selectively utilized to direct spatial and temporal gene expression patterns during differentiation remains to be elucidated but it is clear that regulated changes in higher-order genomic architecture plays a fundamental role. Specifically, long range interactions within and between chromosomes and the position of chromosome territories in the nucleus are controlled by TADs and LADs respectively, but the relationship between these genomic organizers remains poorly understood Overall design: We analyzed the large-scale spatial reorganization of chromatin by generating matched Hi-C and nuclear lamin-chromatin contact datasets throughout a dual adipose/neuronal induction of human primary adipose stem cells. We have mapped Hi-C (TADs) and lamin-associated domains (LADs) in multiple steps during adipose stem cell differentiation to characterize the spatial and temporal link between genomic architecture and gene expression. We identify a new level of 4D genomic organization involving a long-range clustering of individual TADs or TAD pairs into TAD cliques. LADs appear to regulate their formation. (ASCs). We unveil a lineage-specific dynamic assembly and disassembly of repressive cliques of linearly non-contiguous TADs, and a time course-coupled relationship between TAD clique size and lamina association. Our findings reveal a new level of developmental genome organization and provide an overview of large-scale changes in the 4D nucleome during lineage-specific differentiation.
Publication Title
Long-range interactions between topologically associating domains shape the four-dimensional genome during differentiation.
Sample Metadata Fields
No sample metadata fields
View Samples- Homo sapiens
- 12 Downloadable Samples
- Affymetrix Human Gene 1.0 ST Array (hugene10st)
Description
To clarify mineralcorticoid receptor and glucocorticoid receptor-dependent gene networks in decidualizing human endometrial stromal cells.
Publication Title
Induction of 11β-HSD 1 and activation of distinct mineralocorticoid receptor- and glucocorticoid receptor-dependent gene networks in decidualizing human endometrial stromal cells.
Sample Metadata Fields
Sex, Age, Specimen part, Treatment
View Samples- Homo sapiens
- 40 Downloadable Samples
- Illumina Genome Analyzer II
Description
Background: West Nile virus is an emerging infection of biodefense concern and there are no available treatments or vaccines. Here we used a high-throughput method based on a novel gene expression analysis, RNA-Seq, to give a global picture of differential gene expression by primary human macrophages of 10 healthy donors infected in vitro with WNV. Results: From a total of 50 million reads per sample, we employed a Bayesian hierarchical mixture model to identify 4,026 transcripts that were differentially expressed after infection. Both predicted and novel gene changes were detected, as were gene isoforms, and while many of the genes were expressed by all donors, some were unique. Knock-down of genes not previously known to be associated with WNV resistance identified their critical role in control of viral infection. Conclusions: Our study distinguishes both common gene pathways as well as novel cellular responses. Such analysis will be valuable for translational studies of susceptible and resistant individuals -- and for targeting therapeutics -- in multiple biological settings. Overall design: Differential gene expression by primary human macrophages of 10 healthy donors infected in vitro with WNV were generated by RNA-Seq.
Publication Title
Identification of genes critical for resistance to infection by West Nile virus using RNA-Seq analysis.
Sample Metadata Fields
Specimen part, Treatment, Subject
View Samples- Mus musculus
- 2 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
We established a novel EGFP reporter mouse line (named Tg(ETAR-EGFP)14Imeg), which enables the placode-derived inner ear sensory cell lineage to be visualized and monitored. At E10.5, EGFP expression was detected in the ventral and dorsomedial region of the otocyst.
Publication Title
Establishment of mice expressing EGFP in the placode-derived inner ear sensory cell lineage and FACS-array analysis focused on the regional specificity of the otocyst.
Sample Metadata Fields
Specimen part
View Samples- Mus musculus
- 6 Downloadable Samples
- Affymetrix Mouse Gene 1.0 ST Array (mogene10st)
Description
Huntingtons disease (HD) is a dominantly inherited genetic disease caused by mutant huntingtin (htt) protein with expanded polyglutamine tracts. A neuropathological hallmark of HD is the presence of neuronal inclusions of mutant htt. p62 is an important regulatory protein in selective autophagy, a process by which aggregated proteins are degraded, and it is associated with several neurodegenerative disorders including HD. Here we investigated the effect of p62 depletion in three HD model mice: R6/2, HD190QG and HD120QG mice. We found that loss of p62 in these models led to longer lifespans and reduced nuclear inclusions, although cytoplasmic inclusions increased with polyglutamine length. In mouse embryonic fibroblasts (MEFs) with or without p62, mutant htt with a nuclear localization signal (NLS) showed no difference in nuclear inclusion between the two MEF types. In the case of mutant htt without NLS, however, p62 depletion increased cytoplasmic inclusions. Furthermore, to examine the effect of impaired autophagy in HD model mice, we crossed R6/2 mice with Atg5 conditional knockout mice. These mice also showed decreased nuclear inclusions and increased cytoplasmic inclusions, similar to HD mice lacking p62. These data suggest that the genetic ablation of p62 in HD model mice enhances cytoplasmic inclusion formation by interrupting autophagic clearance of polyQ inclusions. This reduces polyQ nuclear influx and paradoxically ameliorates disease phenotypes by decreasing toxic nuclear inclusions.
Publication Title
Depletion of p62 reduces nuclear inclusions and paradoxically ameliorates disease phenotypes in Huntington's model mice.
Sample Metadata Fields
No sample metadata fields
View Samples