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Synaptosome proteome IGF2 enhancer knockout mice

ABSTRACT: We identified an enhancer element near IGF2 locus that is possibly involved with dopamine function and schizophrenia. A knockout mouse was generated for the enhancer element in the IGF2 locus. We then characterized the striatal synaptosomes ( i.e. biological fraction representing pre- post synaptic nerve terminal)by mass spectometry from WT and Igf2 enhancer KO mice.

OTHER RELATED OMICS DATASETS IN: GSE120423GSE112524GSE113093GSE112523GSE112179GSE112525

INSTRUMENT(S): Q Exactive

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Brain

SUBMITTER: Bryan Killinger

LAB HEAD: Viviane Labrie

PROVIDER: PXD012786 | Pride | 2019-05-31

REPOSITORIES: Pride

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			Action	DRS
	20180814_05_3bryan-fx12.mgf	Mgf
	20180814_05_3bryan-fx12.pride.mgf.gz	Mgf
	20180814_05_3bryan-fx12.raw	Raw
	20180814_06_3bryan-fx39.mgf	Mgf
	20180814_06_3bryan-fx39.pride.mgf.gz	Mgf

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Publications

Differential methylation of enhancer at IGF2 is associated with abnormal dopamine synthesis in major psychosis.

Pai Shraddha S Li Peipei P Killinger Bryan B Marshall Lee L Jia Peixin P Liao Ji J Petronis Arturas A Szabó Piroska E PE Labrie Viviane V

Nature communications 20190503 1

Impaired neuronal processes, including dopamine imbalance, are central to the pathogenesis of major psychosis, but the molecular origins are unclear. Here we perform a multi-omics study of neurons isolated from the prefrontal cortex in schizophrenia and bipolar disorder (n = 55 cases and 27 controls). DNA methylation, transcriptomic, and genetic-epigenetic interactions in major psychosis converged on pathways of neurodevelopment, synaptic activity, and immune functions. We observe prominent hypo ...[more]

PMID: 31053723

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Genomic context sensitizes regulatory elements to genetic disruption [DNAse-seq]

Project description:Enhancer function is frequently investigated piecemeal using truncated reporter assays or single deletion analysis, thus it remains unclear to what extent their function is influenced by surrounding genomic context. Using our Big-IN technology for targeted integration of large DNAs, we analyzed the regulatory architecture of the Igf2/H19 locus, a paradigmatic model of enhancer selectivity. We assembled payloads containing a 157-kb functional Igf2/H19 locus and engineered mutations to genetically direct CTCF occupancy at the imprinting control region (ICR) that switches the target gene of the H19 enhancer cluster. Contrasting the activity of payloads delivered to the endogenous locus or to a safe harbor locus (Hprt) revealed that the functional elements comprising the Igf2/H19 locus are highly sensitive to their native context. Exchanging components of the Igf2/H19 locus with the well-studied Sox2 locus showed that the H19 enhancer cluster in particular functioned poorly out of context, and required its native surroundings to activate Sox2 expression. Conversely, the Sox2 locus control region (LCR) could activate both Igf2 and H19 outside its native context, but its activity was only partially modulated by CTCF occupancy at the ICR. Analysis of regulatory DNA actuation across different cell types revealed that, while the H19 enhancers are tightly coordinated within their native locus, the Sox2 LCR acts more independently. We show that these enhancer clusters typify broader classes of loci genome-wide. Our results show that unexpected dependencies may influence even the most studied functional elements, and our synthetic regulatory genomics approach permits large-scale manipulation of complete loci to investigate how locus architecture relates to function.

2024-03-13 | GSE241707 | GEO

Genomic context sensitizes regulatory elements to genetic disruption [DNA]

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Genomic context sensitizes regulatory elements to genetic disruption [CUT&RUN]

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Phosphodiesterase 10A inhibition improves cortico-basal ganglia function in Huntington’s disease models

Project description:Using Huntington’s disease (HD) mouse models that quantitatively replicate the reduction of striatal Phoshodiesterase 10 (PDE10) levels in manifest Huntington’s disease patients, we demonstrate the potential therapeutic benefit of PDE10 inhibition on correcting basal ganglia circuitry deficits thought to drive disease symptomology in patients. PDE10 inhibition acutely restored corticostriatal input and boosted cortically driven indirect pathway activity in HD models with compromised PDE10 levels. We show that cyclic nucleotide signaling processes are impaired in the models, and that elevation of both the cAMP and cGMP nucleotides afforded by PDE10 inhibition are required for this rescue. Global phosphoproteomic profiling of striatal proteins in response to PDE10 inhibition provide novel information on the plausible neural substrates responsible for the improvement. Finally, we show that long-term chronic treatment of the Q175 knock-in mouse model with PDE10A inhibitors, starting at a presymptomatic age, showed improvements, above and beyond those seen during acute administration, including a partial reversal of striatal deregulated transcripts predominantly driven through activation of the AP-1 and CREB transcription factor complexes, and a prevention of the emergence of some cardinal HD neurophysiological deficits.

2016-12-02 | PXD005138 | Pride

RNA 5'end sequencing in polysome profiling fractions

Project description:It has been shown that in mammalian cells alternative transcription initiation is extensively regulated during development and across cell-types, which confers dynamic transcript 5âUTR repertoire. However it is underexplored how the heterogeneity of 5âUTR isoforms would affect the downstream steps for protein expression, such as translation. To this end, we globally compared the translational profile of distinct mRNA TSS isoforms in mouse fibroblast cells, by combining deep-sequencing based mRNA 5âends profiling and polysome fractionation. We demonstrated the extensive translation regulation conferred by TSS heterogeneity. 5'end sequencing in seven polysome fractions, in two replicates, using Illumina Hiseq2000

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Gene expression in striatums of Foxp2-hum, Foxp2-ko and wild-type mice

Project description:It has been proposed that two amino acid substitutions in the transcription factor FOXP2 have been positively selected during human evolution due to effects on aspects of speech and language. Here, we introduce these substitutions into the endogenous Foxp2 gene.of mice. Although these mice are generally healthy, they have qualitatively different ultrasonic vocalizations, decreased exploratory behavior and decreased dopamine concentrations in the brain suggesting an effect of the humanized Foxp2 allele on basal ganglia. In the striatum, a part of the basal ganglia that is affected in humans with a speech deficit due to one non-functional FOXP2 allele, we find that medium spiny neurons have increased dendrite lengths and increased synaptic plasticity. Since mice carrying one non-functional Foxp2 allele show opposite effects, this suggests that alterations in cortico-basal ganglia circuits might have been important for the evolution of speech and language in humans. In this particular experiment, we investigate the effects of human Foxp2 (Foxp2hum) and the non-functional Foxp2 allele on striatal gene expression in embryonic, young and adult mice. We determined genome-wide gene expression patterns in striatal biopsies from Foxp2hum/hum, Foxp2wt/ko and Foxp2wt/wt mice using high-density oligonucleotide arrays. The animals were derived from two independent FoxP2 knock-in strains and one knock-out strain. In total 71 animals were used, 29 males and 42 females. The mice ages were E16.5, P15, P18, P21 and P95 when sacrificed. The microarrays were processed in totally six batches.

2010-05-22 | E-GEOD-13588 | biostudies-arrayexpress

Mouse Gpr88

Project description:Gpr88 is an orphan G protein-coupled receptor highly expressed in the striatum, a region important for motor control and learning. We developed a mouse lacking this receptor (genotype Gpr88Cre/Cre) by replacing most of the open-reading-frame of the Gpr88 gene with Cre recombinase. When comparing the homozygous knockouts against wild-type mice (Gpr88+/+), we have observed that knockout mice are hyperactive, present motor deficits and impaired cue-based learning. However, the signaling pathways downstream of Gpr88 are unknown. To identify putative downstream factors we designed a microarray experiment to identify gene expression changes in the striata of animals lacking Gpr88.

2012-10-15 | E-MTAB-1282 | biostudies-arrayexpress

Correlation profiling of synaptic sub-fraction proteomes of the mouse brain hippocampus, cortex and cerebellum

Project description:Synaptic transmission forms the main mode of signaling and information integration in the nervous system. Here, we identified and quantified proteins from three brain regions and five biochemical synapse sub-fractions. We identified around 4500 proteins in total, of which about 2000 proteins each were quantified from microsome, P2 fraction, synaptosome, synaptic membrane, and postsynaptic density (PSD). Correlation profiling using these data sets identified synaptic functional groups and showed enrichment of canonical presynaptic proteins in synaptosome, and canonical postsynaptic proteins in PSD. In addition, we detected profound brain region specific differences in the extent of enrichment for some functionally associated proteins, exemplified by different AMPAR subunits and the large differences in spatial distribution of their potential interactors. Furthermore, we revealed novel PSD proteins PLEKHA5 and ADGRA1, which using super-resolution microscopy on primary neuronal culture were confirmed to reside in the PSD.

2017-09-25 | PXD005634 | Pride

Striatum of Huntington's disease model mice [Affymetrix data]

Project description:Evaluation of transcriptional changes in the striatum may be an effective approach to understanding the natural history of changes in expression contributing to the pathogenesis of Huntington disease (HD). We have performed genome-wide expression profiling of the YAC128 transgenic mouse model of HD at 12 and 24 months of age using two platforms in parallel; Affymetrix and Illumina. We performed gene expression profiling on the same striatal mRNA across both platforms. Transgenic mice expressing human HD huntingtin with 120 CAG repeats (YAC128) and wildtype littermates were used for the described experiments. The mice were group housed in polystyrene cages under a normal light-dark cycle (6 am to 8 pm) in a clean facility and with free access to water and standard rodent chow. All experiments were performed in accordance with the University of British Columbia animal care committee. Striatal tissue was collected from 12 and 24 month old YAC128 mice and wildtype littermates.

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Proteomic analysis of gliosomes from mouse brain for investigation of glial membrane proteins

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