Ubiquitin Ligase (UBE4B) and Lysine-Specific Demethylase (LSD1) are post-translational modifying enzymes affecting lysine ubiquitination and methylation of several important regulatory proteins, and are synergisticaly important for protein quality control. To inwestigate their role in cell signaling, we analyzed global mRNA levels in HEK293T cells that were knocked down with shRNAs against UBE4B, LSD1, both UBE4B and LSD1, and non-targeting control (CTRL).
Regulation of protein quality control by UBE4B and LSD1 through p53-mediated transcription.
Cell line, Time
View SamplesUterine leiomyomata, or fibroids, are benign tumors of the uterine myometrium that significantly affect up to 30% of reproductive-age women. Despite being the primary cause of hysterectomy in the United States, accounting for up to 200,000 procedures annually, the etiology of leiomyoma remains largely unknown. Due to the lack of an effective medicinal therapy for these tumors, this disease continues to have a tremendous negative impact on womens health. As a basis for understanding leiomyoma pathogenesis and identifying targets for pharmacotherapy, we conducted transcriptional profiling of leiomyoma and unaffected myometrium from humans and Eker rats, the best characterized preclinical model of leiomyoma. A global comparison of mRNA from leiomyoma versus myometrium in human and rat identified a highly significant overlap of dysregulated gene expression in leiomyoma. An unbiased pathway analysis using a method of gene set enrichment based on the Sigpathway algorithm detected the mammalian target of rapamycin (mTOR) pathway as one of the most highly upregulated pathways in both human and rat tumors. Activation of this pathway was confirmed in both human and rat leiomyomata at the protein level via Western. Inhibition of mTOR in female Eker rats with the rapamycin analog WAY-129327 for 2 weeks decreased mTOR signaling and cell proliferation in tumors, and treatment for 4 months significantly decreased tumor incidence, multiplicity and size. These results identify dysregulated mTOR signaling as a component of leiomyoma etiology across species and directly demonstrate the dependence of these tumors on mTOR signaling for growth in the Eker rat. Modulation of this pathway warrants additional investigation as a potential therapy for uterine leiomyoma.
Comparison of human and rat uterine leiomyomata: identification of a dysregulated mammalian target of rapamycin pathway.
No sample metadata fields
View SamplesHow G4C2 repeat expansions in C9orf72 cause frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) is not understood. Here, we report the first mouse model to express poly(PR), a dipeptide repeat protein synthesized from expanded G4C2 repeats. Expression of GFP-(PR)50 throughout the mouse brain yielded progressive brain atrophy, neuron5 loss, loss of poly(PR)-positive cells and gliosis, culminating in motor and memory impairments. We found that poly(PR) bound DNA, localized to heterochromatin, and caused abnormal histone methylation, lamin invaginations, decreases in HP1a expression, and disruptions of HP1a liquid phases. These aberrations of histone methylation, lamins and HP1a, which regulate heterochromatin structure and gene expression, were accompanied by repetitive element10 expression and double-stranded RNA accumulation. Thus, we uncover new mechanisms by which poly(PR) contributes to c9FTD/ALS pathogenesis. Overall design: Examination of transcriptome profiles using RNA-seq on 3 month old mice expressing PR and GR polypetides with an AAV expression vector. The Poly(PR) analysis consisted of 7 mice expressing AAV-GFP-(PR)50 and 4 AAV-GFP harvest-matched controls. The Poly(GR) analysis consisted of 4 mice expressing AAV-GFP-(GR)100 and 4 AAV-GFP harvest-matched controls.
Heterochromatin anomalies and double-stranded RNA accumulation underlie <i>C9orf72</i> poly(PR) toxicity.
Sex, Age, Cell line, Subject
View SamplesGenetic variation modulating risk of sporadic Parkinson's disease (PD) has been primarily explored through genome wide association studies (GWAS). However, like many other common genetic diseases, the impacted genes remain largely unknown. Here, we used single-cell RNA-seq to characterize dopaminergic (DA) neuron populations in the mouse brain at embryonic and early postnatal timepoints. These data facilitated unbiased identification of DA neuron subpopulations through their unique transcriptional profiles, including a novel postnatal neuroblast population and substantia nigra (SN) DA neurons. We use these population-specific data to develop a scoring system to prioritize candidate genes in all 49 GWAS intervals implicated in PD risk, including known PD genes and many with extensive supporting literature. As proof of principle, we confirm that the nigrostriatal pathway is compromised in Cplx1 null mice. Ultimately, this systematic approach establishes biologically pertinent candidates and testable hypotheses for sporadic PD, informing a new era of PD genetic research. Overall design: 473 single cell RNA-Seq samples from sorted mouse Th-eGFP+ dopaminergic neurons collected at two timepoints from three distinct brain regions.
Single-Cell RNA-Seq of Mouse Dopaminergic Neurons Informs Candidate Gene Selection for Sporadic Parkinson Disease.
Specimen part, Subject
View SamplesThe goal of this study was to identify candidate genes that may influence alcohol consumption by comparing gene expression in 5 brain regions of alcohol-nave iP and P.NP rats.
Candidate genes for alcohol preference identified by expression profiling in alcohol-preferring and -nonpreferring reciprocal congenic rats.
Specimen part
View SamplesA highly significant quantitative trait locus (QTL) that influenced alcohol preference was identified in the iP/iNP rats on chromosome 4.
Identification of candidate genes for alcohol preference by expression profiling of congenic rat strains.
No sample metadata fields
View SamplesInfection is a major complication and cause of mortality and morbidity after acute stroke however the mechanisms are poorly understood. After experimental stroke the microarchitecture and cellular composition of the spleen are extensively disrupted resulting in deficits to immune function.
Experimental Stroke Differentially Affects Discrete Subpopulations of Splenic Macrophages.
Specimen part, Treatment
View SamplesRNA-seq with male and female juvenile and adult spinal cords Overall design: RNA was isolated from 4 week and 8 week spinal cords for sequencing
Age and Sex-Related Changes to Gene Expression in the Mouse Spinal Cord.
Sex, Age, Specimen part, Cell line, Subject
View SamplesMurine testis developmental time course created from tissue samples collected from birth through adulthood and hybridized to MGU74v2 A, B, and C chips in duplicate
The murine testicular transcriptome: characterizing gene expression in the testis during the progression of spermatogenesis.
No sample metadata fields
View SamplesIn order to define the targets of two miRNA overexpressed in NK cells in CFS/ME paitents, miRNA precursors for hsa-miR-99b and hsa-miR-330-3p were transfected in to buffy coat derived Natural Killer cells isolated by negative magnetic selection.
MicroRNAs hsa-miR-99b, hsa-miR-330, hsa-miR-126 and hsa-miR-30c: Potential Diagnostic Biomarkers in Natural Killer (NK) Cells of Patients with Chronic Fatigue Syndrome (CFS)/ Myalgic Encephalomyelitis (ME).
Specimen part, Disease, Disease stage
View Samples