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SRP064190
Mus musculus
12 Downloadable Samples
Illumina HiSeq 2500
Description
Despite significant advances in our understanding of the biology determining systemic energy homeostasis, the treatment of obesity remains a medical challenge. Activation of AMP-activated protein kinase (AMPK) has been proposed as an attractive strategy for the treatment of obesity and its complications. AMPK is a conserved, ubiquitously expressed, heterotrimeric serine/threonine kinase whose short-term activation has multiple beneficial metabolic effects. Whether these translate into long-term benefits for obesity and its complications is unknown. Here, we observe that mice with chronic AMPK activation, resulting from mutation of the AMPK ?2 subunit, exhibit ghrelin signalling-dependent hyperphagia, obesity and impaired pancreatic islet insulin secretion. Humans bearing the homologous mutation manifest a congruent phenotype. Our studies highlight that long-term AMPK activation can have adverse metabolic consequences with implications for pharmacological strategies seeking to chronically activate AMPK systemically to treat metabolic disease. Overall design: Transcriptomic profiling of the hypothalamic arcuate nucleus from AMPK ?2 R299Q knock-in mice
Publication Title
Chronic Activation of γ2 AMPK Induces Obesity and Reduces β Cell Function.
Sample Metadata Fields
Specimen part, Cell line, Subject
View Samples- Drosophila melanogaster
- 12 Downloadable Samples
Affymetrix Drosophila Genome 2.0 Array (drosophila2)
Description
Innate immune responses contributed to the containment of intestinal microbes.
Publication Title
Constitutive Immune Activity Promotes Tumorigenesis in Drosophila Intestinal Progenitor Cells.
Sample Metadata Fields
Specimen part
View Samples- Mus musculus
- 12 Downloadable Samples
Description
We report a novel technique, Affinity-seq, that for the first time identifies both the genome-wide binding sites of DNA-binding proteins and quantitates their relative affinities. We have applied this in vitro technique to PRDM9, the zinc-finger protein that activates genetic recombination, obtaining new information on the regulation of hotspots, whose locations and activities determine the recombination landscape. We identified 31,770 binding sites in the mouse genome for the PRDM9Dom2 variant. Comparing these results with hotspot usage in vivo, we find that less than half of potential PRDM9 binding sites are utilized in vivo. We show that hotspot usage is increased in actively transcribed genes and decreased in genomic regions containing H3K9me2/3 histone marks or bound to the nuclear lamina. These results show that a major factor determining whether a binding site will become an active hotspot and what its activity will be are constraints imposed by prior chromatin modifications on the ability of PRDM9 to bind to DNA in vivo. These constraints lead to the presence of long genomic regions depleted of recombination. Overall design: The terminal zinc finger domain of PRDM9Dom2 (PRDM9?ZnF1Dom2, 412–847 aa), the allele present in C57BL/6J (B6) mice was cloned and tagged with 6His-HALO and then expressed in E. coli. DNA sheared to 180–200 bp is provided in considerable excess to provide competition between DNA binding sites. Following binding, DNA–protein complexes are then isolated on streptavidin beads and the DNA extracted for deep sequencing. Two replicate Affinity-seq samples were sequenced at 100-bp reads using the Illumina HiSeq 2500. Alignments to the mm9 mouse genome were obtained utilizing BWA v1.2.3 with default parameters and reads which failed to align to unique positions in the genome were discarded. Peaks were called individually for the two replicates with MACS2 at a p value threshold of 0.01 utilizing a control dataset obtained by sequencing the input DNA and subsequently compared, leading ultimately to combining the two replicates for definitive analysis.
Publication Title
Affinity-seq detects genome-wide PRDM9 binding sites and reveals the impact of prior chromatin modifications on mammalian recombination hotspot usage.
Sample Metadata Fields
No sample metadata fields
View Samples- Zea mays
- 10 Downloadable Samples
- Illumina HiSeq 2000, Illumina Genome Analyzer IIx
Description
Maize LEAFBLADELESS1 (LBL1) and Arabidopsis SUPPRESSOR OF GENE SILENCING3 (SGS3) play orthologous roles in the biogenesis of 21 nucleotide trans-acting short-interfering RNAs (tasiRNAs). The phenotypes conditioned by mutation of lbl1 and SGS3 are, however, strikingly different, suggesting that the activities of these small RNA biogenesis components, or the tasiRNAs and their targets might not be entirely conserved. To investigate the basis for this phenotypic variation, we compared the small RNA content between wild-type and lbl1 seedling apices. We show that LBL1 affects all major classes of small RNAs, and reveal unexpected crosstalk between tasiRNA biogenesis and other small RNA pathways regulating miRNAs, retrotransposons, and DNA transposons. We further identified genomic regions generating phased siRNAs, including numerous loci generating 22-nt phased small RNAs from long hairpin RNAs or overlapping antisense transcripts not previously described in other plant species. By combining both analyses, we identified nine TAS loci, all belonging to the conserved TAS3 family. Contrary to other plant species, no TAS loci targeted by a single miRNA were identified. Information from target prediction, RNAseq, and PARE analyses identified the tasiARFs as the major functional tasiRNAs in the maize vegetative apex where they regulate expression of ARF3 homologs. As such, divergence in TAS pathways is unlikely to account for the distinct phenotypes of tasiRNA biogenesis mutants in Arabidopsis and maize. Instead, the data suggests variation in the spatiotemporal regulation of ARF3, or divergence in its function, as a plausible basis for the dramatic phenotypic differences observed upon mutation of SGS3/lbl1 in Arabidopsis and maize. Overall design: An analysis of tasiRNA biogenesis, activity, and contribution to developmental phenotypes in the maize leaf. Data generated includes small RNA sequencing data and mRNA sequencing data. All data was generated in both wild type and lbl1 mutant maize leaf apices. Three replicates were generated for each genotype for the small RNA data. Two of these replicates were also used for the RNA-seq data.
Publication Title
Genome-wide analysis of leafbladeless1-regulated and phased small RNAs underscores the importance of the TAS3 ta-siRNA pathway to maize development.
Sample Metadata Fields
Age, Specimen part, Subject
View Samples- Homo sapiens
- 16 Downloadable Samples
- Affymetrix Human Gene 1.0 ST Array (hugene10st)
Description
Differential expression was used to access gene differences after Entamoeba histolytica infection.
Publication Title
The expression of REG 1A and REG 1B is increased during acute amebic colitis.
Sample Metadata Fields
Specimen part
View Samples- Homo sapiens
- 12 Downloadable Samples
- Affymetrix Human Gene 1.0 ST Array (hugene10st)
Description
In this work, we isolated and characterized a novel cell population derived from human amniotic fluid cells (hAKPC-P), and we differentiated them into podocytes.
Publication Title
A novel source of cultured podocytes.
Sample Metadata Fields
Specimen part, Cell line
View Samples- Homo sapiens
- 21 Downloadable Samples
- Affymetrix Human Genome U133A 2.0 Array (hgu133a2)
Description
The full complement of molecular pathways contributing to Parkinsons disease (PD) pathogenesis remains unknown. Here, to address this issue, we began by using a high-resolution variant of functional magnetic resonance imaging (fMRI) to pinpoint brainstem regions differentially affected by, and resistant to, the disease. Then, relying on the imaging information as a guide, we profiled gene expression levels of postmortem brain samples and used a factorial statistical model to identify a disease related decrease in the expression of the polyamine enzyme spermidine/spermine N1-acetyltransferase 1 (SAT1). Next, a series of studies were performed to confirm the pathogenic relevance of this finding. First, to test for a causal link between polyamines and -synuclein toxicity, we investigated a yeast model expressing -synuclein. Polyamines were found to enhance the toxicity of -synuclein, and an unbiased genome-wide screen for modifiers of -synuclein toxicity identified Tpo4, a member of a family of proteins responsible for polyamine transport. Second, to test for a causal link between SAT1 activity and PD histopathology we investigated a mouse model expressing -synuclein. DENSPM (N1, N11-diethylnorspermine), a polyamine analog that increases SAT1 activity, was found to reduce PD histopathology, while Berenil (diminazene aceturate), a pharmacological agent that reduces SAT1 activity, worsened the histopathology. Third, we genotyped PD patients and controls and isolated a rare but novel variant in the SAT1 gene, although the functional significance of this genetic variant was not identified. Taken together, the results suggest that the polyamine pathway contributes to PD pathogenesis.
Publication Title
Polyamine pathway contributes to the pathogenesis of Parkinson disease.
Sample Metadata Fields
Sex, Age, Subject
View Samples- Mus musculus
- 7 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
NF-κB inhibition rescues cardiac function by remodeling calcium genes in a Duchenne muscular dystrophy model.
Sample Metadata Fields
Age
View Samples- Mus musculus
- 7 Downloadable Samples
Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
We found genetic deletion of IKK in mdx cardiomyocytes improved cardiac function and normalized calcium transients. We used microarrays to profile gene expression in hearts of mdx mice with intact IKK signaling and hearts of mdx mice with IKK-deficient cardiomyocytes to identify genes differentially regulated by NF-[kappa]B. signaling in dystrophic hearts.
Publication Title
NF-κB inhibition rescues cardiac function by remodeling calcium genes in a Duchenne muscular dystrophy model.
Sample Metadata Fields
Age
View Samples- Danio rerio
- 24 Downloadable Samples
- Affymetrix Zebrafish Genome Array (zebrafish)
Description
Exposure to environmental contaminants can disrupt normal development of the early vertebrate skeleton. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) impairs craniofacial skeletal development across many vertebrate species and its effects are especially prominent in early life stages of fish. TCDD activates the aryl hydrocarbon receptor (AHR), a transcription factor that mediates most if not all TCDD responses. We investigated the transcriptional response in the developing zebrafish jaw following TCDD exposure using DNA microarrays. Zebrafish larvae were exposed to TCDD at 96 h postfertilization (hpf) and jaw cartilage tissue was harvested for microarray analysis at 1, 2, 4 and 12 h postexposure (hpe). Numerous chondrogenic transcripts were misregulated by TCDD in the jaw. Comparison of transcripts altered by TCDD in jaw with transcripts altered in embryonic heart showed that the transcriptional responses in the jaw and the heart were strikingly different. Sox9b, a critical chondrogenic transcription factor, was the most significantly reduced transcript in the jaw. We hypothesized that the TCDD reduction of sox9b expression plays an integral role in affecting formation of the embryonic jaw. Morpholino knock down of sox9b expression demonstrated that partial reduction of sox9b expression alone was sufficient to produce a TCDD-like jaw phenotype. Heterozygous sox9b deletion mutant embryos were sensitized to TCDD. Lastly, embryos injected with sox9b mRNA and then exposed to TCDD blocked TCDD-induced jaw toxicity in approximately 14% of sox9b-injected embryos. These results suggest that reduced sox9b expression in TCDD-exposed zebrafish embryos contributes to jaw malformation.
Publication Title
Aryl hydrocarbon receptor-mediated down-regulation of sox9b causes jaw malformation in zebrafish embryos.
Sample Metadata Fields
No sample metadata fields
View Samples