Austism spectrum disorder (ASD) is a heterogeneous behavioral disease most commonly characterized by severe impairment of social engagement and the presence of repetitive activities. The molecular etiology of ASD is still largely unknown despite a strong genetic component. Part of the difficulty in turning genetics into disease mechanisms and potentially new therapeutics is the sheer number and diversity of the genes that have been associated with ASD and ASD symptoms. The goal of this work is to use shRNA-generated models of genetic defects proposed as causative for ASD to identify the common pathways that might explain how they produce a common clinical outcome. Transcript levels of Mecp2, Mef2a, Mef2d, Fmr1, Nlgn1, Nlgn3, Pten, and Shank3 were knocked-down in mouse primary neuron cultures using shRNA/lentivirus constructs. Whole genome expression analysis was conducted for each of the knock-down cultures as well as a mock-transduced culture and a culture exposed to a lentivirus expressing luciferase. Gene set enrichment and a causal reasoning engine were employed to indentify pathway level perturbations generated by the transcript knock-down. Quantitation of the shRNA targets confirmed the successful knock-down at the transcript and protein levels of at least 75% for each of the genes. After subtracting out potential artifacts caused by transfection and viral infection, gene set enrichment and causal reasoning engine analysis showed that a significant number of gene expression changes mapped to pathways associated with neurogenesis, long-term potentiation, and synaptic activity. This work demonstrates that despite the complex genetic nature of ASD, there are common molecular mechanisms that connect many of the best established autism candidate genes. By identifying the key regulatory checkpoints in the interlinking transcriptional networks underlying autism, we are better able to discover the ideal points of intervention that provide the broadest efficacy across the diverse population of autism patients.
Transcriptomic analysis of genetically defined autism candidate genes reveals common mechanisms of action.
Specimen part, Treatment
View SamplesUsing RNA-Seq, we compared the transcriptomes of muscle from wild type C57BL/6J or Zp407 transgenic mice. Overall design: Biceps femoris were stored in RNAlater from 5-week-old overnight-fasted male mice. 5 mice were used per group for wild type and Zp407 transgenic mice.
Zinc finger protein 407 overexpression upregulates PPAR target gene expression and improves glucose homeostasis in mice.
Sex, Age, Specimen part, Subject
View SamplesGlucocorticoids have major effects on adipose tissue metabolism. To study tissue mRNA expression changes induced by chronic elevated endogenous glucocorticoids, we performed RNA sequencing on subcutaneous adipose tissue from patients with Cushing's disease (n=5) compared to patients with non-functioning pituitary adenomas (n=11). We found higher expression of transcripts involved in several metabolic pathways, including lipogenesis, proteolysis and glucose oxidation as well as decreased expression of transcripts involved in inflammation and protein synthesis. To further study this in a model system, we subjected mice to dexamethasone treatment for 12 weeks and analyzed their inguinal (subcutaneous) fat pads, which led to similar findings. Additionally, mice treated with dexamethasone showed drastic decreases in lean body mass as well as increased fat mass, further supporting the human transcriptomic data. These data provide insight to transcriptional changes that may be responsible for the co-morbidities associated with chronic elevations of glucocorticoids Overall design: DESIGN: Patients with cushing's (n=5) or non-functioning pituitary adenoma (n=11) were prospectively observed from March 2011 to June 2012.
Gene expression changes in subcutaneous adipose tissue due to Cushing's disease.
No sample metadata fields
View SamplesTo determine whether adding Decipher to standard risk stratification tools (CAPRA-S and Stephenson nomogram) improves accuracy in prediction of metastatic disease within 5 years after surgery in men with adverse pathologic features after RP.
A genomic classifier improves prediction of metastatic disease within 5 years after surgery in node-negative high-risk prostate cancer patients managed by radical prostatectomy without adjuvant therapy.
Age
View SamplesObesity is a heterogeneous conditions comprising obese individuals with metabolic disorders (termed metabolically unhealthy obese; MUO) and obese individuals who are metabolically healthy (termed metabolically healthy obese; MHO).
Serum and adipose tissue amino acid homeostasis in the metabolically healthy obese.
Specimen part, Disease, Disease stage
View SamplesTo characterize genes, pathways, and transcriptional regulators enriched in the mouse cornea, we compared the expression profiles of whole mouse cornea, bladder, esophagus, lung, proximal small intestine, skin, stomach, and trachea.
The Ets transcription factor EHF as a regulator of cornea epithelial cell identity.
Specimen part
View SamplesThis SuperSeries is composed of the SubSeries listed below.
The Ets transcription factor EHF as a regulator of cornea epithelial cell identity.
Age, Specimen part
View SamplesWhile the mouse cornea has been well characterized morphologically, the transcriptional changes have not been described in detail. To characterize the genes, pathways, and transcriptional regulators involved in mouse cornea development and aging, we isolated whole cornea from wildtype CB6 mice at several developmental timepoints and every 6 months in the adult. Corneal epithelium and stroma were isolated at one timepoint to provide insights into the genes that are unique to each tissue.
The Ets transcription factor EHF as a regulator of cornea epithelial cell identity.
Age, Specimen part
View SamplesmRNA expression differences between the liver and kidney of an adult male (homo sapien) were investigated using three technical replicates.
RNA-seq: an assessment of technical reproducibility and comparison with gene expression arrays.
No sample metadata fields
View SamplesEhf is a transcriptional regulator that is highly expressed and enriched in corneal epithelium. To gain insights into the role of Ehf in the corneal epithelium, we performed siRNA knockdown of Ehf in primary human corneal epithelial cells.
The Ets transcription factor EHF as a regulator of cornea epithelial cell identity.
Specimen part
View Samples