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SRP045495
Mus musculus
4 Downloadable Samples
Illumina HiSeq 2000
Description
Naturally occurring variations of Polycomb Repressive Complex 1 (PRC1) comprise a core assembly of Polycomb group proteins and additional factors that include, surprisingly, Autism Susceptibility Candidate 2 (AUTS2). While AUTS2 is often disrupted in patients with neuronal disorders, the underlying mechanism is unclear. We investigated the role of AUTS2 as part of a previously identified PRC1 complex (PRC1-AUTS2), and in the context of neurodevelopment. In contrast to the canonical role of PRC1 in gene repression, PRC1-AUTS2 activates transcription. Biochemical studies demonstrate that the CK2 component of PRC1-AUTS2 thwarts PRC1 repressive activity and AUTS2-mediated recruitment of P300 leads to gene activation. ChIP-seq of AUTS2 shows that it regulates neuronal gene expression through promoter association. Conditional CNS targeting of Auts2 in a mouse model leads to various developmental defects. These findings reveal a natural means of subverting PRC1 activity, linking key epigenetic modulators with neuronal functions and diseases. Overall design: mRNA profiles of P1 brain from wild type mice were generated by deep sequencing
Publication Title
An AUTS2-Polycomb complex activates gene expression in the CNS.
Sample Metadata Fields
No sample metadata fields
View Samples- Homo sapiens
- 12 Downloadable Samples
Affymetrix Human Genome U133A Array (hgu133a)
Description
We disprove that the impaired Myd88-dependent proinflammatory response of neonatal monocytes is a correlate for immaturity and confirm it as display of transient alarmin-mediated stress tolerization. We find a strong inducibility of TRIF-dependent genes in neonatal monocytes by LPS but a barely detectable expression at baseline.
Publication Title
S100-alarmin-induced innate immune programming protects newborn infants from sepsis.
Sample Metadata Fields
Specimen part, Treatment
View Samples- Mus musculus
- 12 Downloadable Samples
- Affymetrix Mouse Expression 430A Array (moe430a)
Description
The neuronal ceroid lipofuscinoses (NCL) are a group of childhood inherited neurodegenerative disorders characterized by blindness, early dementia and pronounced cortical atrophy. The similar pathological and clinical profiles of different forms of NCL suggest that common disease mechanisms may be involved. Here, we have performed quantitative gene expression profiling of cortex from targeted knock out mice produced for Cln1 and Cln5 to explore NCL-associated molecular pathways. Combined microarray datasets from both mouse models exposed a common affected pathway: genes regulating cytoskeletal dynamics and neuronal growth cone stabilization display similar aberrations. We analyzed locus specific gene expression and showed regional clustering of Cln1 and three major genes of this pathway, further supporting a close functional relationship between the corresponding gene products, Cap1, Ptprf and Ptp4a2. The evidence from the gene expression data was substantiated by immunohistochemical staining data of Cln1-/- and Cln5-/- cortical neurons. These primary neurons displayed abnormalities in beta-tubulin and actin as well as abnormal intracellular distribution of growth cone associated proteins GAP-43, synapsin and Rab3. Our data provide the first evidence for a common molecular pathogenesis behind neuronal degeneration in CLN1 and CLN5. Since CLN1 and CLN5 code for proteins with distinct functional roles these data may have implications for other forms of NCL.
Publication Title
Brain gene expression profiles of Cln1 and Cln5 deficient mice unravels common molecular pathways underlying neuronal degeneration in NCL diseases.
Sample Metadata Fields
Sex, Age, Specimen part, Disease
View Samples- Mus musculus
- 24 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
Studies investigating the causes of autism spectrum disorder (ASD) point to genetic as well as epigenetic mechanisms of the disease. Identification of epigenetic processes that contribute to ASD development and progression is of major importance and may lead to the development of novel therapeutic strategies. Here we identify the bromodomain and extra-terminal domain containing transcriptional regulators (BETs) as epigenetic drivers of an ASD-like disorder in mice. We found that the pharmacological suppression of the BET proteins by a novel, highly selective and brain-permeable inhibitor, I-BET858, leads to selective suppression of neuronal gene expression followed by the development of an autism-like syndrome in mice. Many of the I-BET858 affected genes have been linked to ASD in humans thus suggesting the key role of the BET-controlled gene network in ASD. Our studies also suggest that environmental factors controlling BET proteins or their target genes may contribute to the epigenetic mechanism of ASD.
Publication Title
Autism-like syndrome is induced by pharmacological suppression of BET proteins in young mice.
Sample Metadata Fields
Specimen part
View Samples- Mus musculus
- 23 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
Polycomb repressive complex 2 (PRC2) silences genes responsible for neurodegeneration.
Sample Metadata Fields
Age, Specimen part
View Samples- Mus musculus
- 23 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
Normal brain function critically depends on the interaction between highly specialized neurons that operate within anatomically and functionally distinct brain regions. The fidelity of neuronal specification is contingent upon the robustness of the transcriptional program that supports the neuron type-specific patterns of gene expression. Changes in neuron type-specific gene expression are commonly associated with neurodegenerative disorders including Huntingtons and Alzheimers disease. The neuronal specification is driven by gene expression programs that are established during early stages of neuronal development and remain in place in the adult brain. Here we show that the Polycomb repressive complex 2 (PRC2), which supports neuron specification during early differentiation, contributes to the suppression of the transcription program that can be detrimental for the adult neuron function. We show that PRC2 deficiency in adult striatal neurons and in cerebellar Purkinje cells impairs the maintenance of neuron-type specific gene expression. The deficiency in PRC2 has a direct impact on a selected group of genes that is dominated by self-regulating transcription factors normally suppressed in these neurons. The age-dependent progressive transcriptional changes in PRC2-deficient neurons are associated with impaired neuronal function and survival and lead to the development of fatal neurodegenerative disorders in mice.
Publication Title
Polycomb repressive complex 2 (PRC2) silences genes responsible for neurodegeneration.
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus
- 16 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
MicroRNA regulates protein expression of cells by repressing translation of specific target messenger transcripts. Loss of the neuron specific microRNA miR-128 in Dopamine D1-receptor expressing neurons in the murine striatum (D1-MSNs) lead to increased neuronal excitability, locomotor hyperactivity and fatal epilepsy.
Publication Title
MicroRNA-128 governs neuronal excitability and motor behavior in mice.
Sample Metadata Fields
No sample metadata fields
View Samples- Homo sapiens
- 8 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
Human strabismic extraocular muscles (EOMs) differ from normal EOMs in structural and functional properties, but the gene expression profile of these two types of human EOM has not been examined. Differences in gene expression may inform about causes and effects of the strabismic condition in humans. Our samples are from human strabismic patients undergoing corrective surgery, and from human organ donors with no history of EOM disease.
Publication Title
Differences in gene expression between strabismic and normal human extraocular muscles.
Sample Metadata Fields
Sex, Specimen part
View Samples- Saccharomyces cerevisiae
- 8 Downloadable Samples
- Affymetrix Yeast Genome 2.0 Array (yeast2)
Description
The needs for rapid and efficient microbial cell factory design and construction are possible through the enabling technology, metabolic engineering, which is now being facilitated by systems biology approaches. Metabolic engineering is often complimented by directed evolution, where selective pressure is applied to a partially genetically engineered strain to confer a desirable phenotype. The exact genetic modification or resulting genotype that leads to the improved phenotype is often not identified or understood to enable further metabolic engineering. In this work we establish proof-of-concept that whole genome high-throughput sequencing and annotation can be used to identify single nucleotide polymorphisms (SNPs) between Saccharomyces cerevisiae strains S288c and CEN.PK113-7D. The yeast strain S288c was the first eukaryote sequenced, serving as the reference genome for the Saccharomyces Genome Database, while CEN.PK113-7D is a preferred laboratory strain for industrial biotechnology research. A total of 13,787 high-quality SNPs were detected between both strains (reference strain: S288c). Considering only metabolic genes (782 of 5,873 annotated genes), a total of 219 metabolism specific SNPs are distributed across 158 metabolic genes, with 85 of the SNPs being non-silent (e.g., encoding amino acid modifications). Amongst metabolic SNPs detected, there was pathway enrichment in the galactose uptake pathway (GAL1, GAL10) and ergosterol biosynthetic pathway (ERG8, ERG9). Physiological characterization confirmed a strong deficiency in galactose uptake and metabolism in S288c compared to CEN.PK113-7D, and similarly, ergosterol content in CEN.PK113-7D was significantly higher in both glucose and galactose supplemented cultivations compared to S288c. Furthermore, DNA microarray profiling of S288c and CEN.PK113-7D in both glucose and galactose batch cultures did not provide a clear hypothesis for major phenotypes observed, suggesting that genotype to phenotype correlations are manifested post-transcriptionally or post-translationally either through protein concentration and/or function. With an intensifying need for microbial cell factories that produce a wide array of target compounds, whole genome high-throughput sequencing and annotation for SNP detection can aid in better reducing and defining the metabolic landscape. This work demonstrates direct correlations between genotype and phenotype that provides clear and high-probability of success metabolic engineering targets. The genome sequence, annotation, and a SNP viewer of CEN.PK113-7D are deposited at www.sysbio.se/cenpk.
Publication Title
Whole genome sequencing of Saccharomyces cerevisiae: from genotype to phenotype for improved metabolic engineering applications.
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus
- 18 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
Using the novel BTK inhibitor PF-303, we model the clinical phenotype of BTK inhibition by systematically examining the impact of PF-303 on the mature immune system in mice autoimmune indications. However, our current knowledge of the role of BTK in immune competence has been gathered in the context of genetic inactivation of btk in both mice and man. Using the novel BTK inhibitor PF-303, we model the clinical phenotype of BTK inhibition by systematically examining the impact of PF-303 on the mature immune system in mice. We implicate BTK in tonic BCR signaling, demonstrate dependence of the T3 B cell subset and IgM surface expression on BTK activity, and find that B1 cells survive and function independently of BTK. While BTK inhibition does not impact humoral memory survival, antigen-driven clonal expansion of memory B cells and antibody secreting cell generation are inhibited. These data define the role of BTK in the mature immune system and mechanistically predict the clinical phenotype of BTK inhibition.
Publication Title
Modeling the clinical phenotype of BTK inhibition in the mature murine immune system.
Sample Metadata Fields
Specimen part
View Samples