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SRP067243
Mus musculus
20 Downloadable Samples
Illumina HiSeq 2000
Description
Analysis of the transcriptional changes in the heart resulting from the loss of cardiac enhancers. As there remains a limited understanding of the phenotypic consequences of enhancer mutations, we examined the impact of loss of function mutations by deleting two enhancers near heart disease genes in mice. In both cases, we observed loss of target gene expression, as well as cardiac phenotypes consistent with heart disease in humans, highlighting the functional importance of enhancers for normal heart function, as well as the potential contribution of enhancer mutations to heart disease. Overall design: Hearts were dissected from wild-type and enhancer-null mice (either embryonic or adult) and processed for deep RNA-seq analysis.
Publication Title
Genome-wide compendium and functional assessment of in vivo heart enhancers.
Sample Metadata Fields
Sex, Specimen part, Cell line, Subject
View Samples- Mus musculus
- 10 Downloadable Samples
- Illumina HiSeq 2000
Description
Mammalian genomes are organized into megabase-scale topologically associated domains (TADs) that have been proposed to represent large regulatory units. Here we demonstrate that disruption of TADs can cause rewiring of long-range regulatory architecture and result in pathogenic phenotypes. We show that distinct human limb malformations are caused by deletions, inversions, or duplications altering the structure of the TAD-spanning WNT6/IHH/EPHA4/PAX3 locus. Using CRISPR/Cas genome editing, we generated mice with corresponding rearrangements. Both in mouse limb tissue and patient-derived fibroblasts, disease-relevant structural changes cause ectopic interactions between promoters and non-coding DNA, and a cluster of limb enhancers normally associated with Epha4 is misplaced relative to TAD boundaries and drives ectopic limb expression of another gene in the locus. Our results demonstrate the functional importance of TADs for orchestrating gene expression via genome architecture and indicate criteria for predicting the pathogenicity of human structural variants, particularly in non-coding regions of the human genome. Overall design: RNA-seq profile of developing distal limbs of mutants and WT animals at E11.5
Publication Title
Disruptions of topological chromatin domains cause pathogenic rewiring of gene-enhancer interactions.
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus
- 15 Downloadable Samples
- Illumina HiSeq 2500, NextSeq 500
Description
Rett syndrome is caused by mutations in the gene encoding methyl-CpG binding protein 2 (MECP2), an epigenetic regulator of mRNA transcription. Here we report a test of the hypothesis of shared pathophysiology of Rett syndrome and fragile X, another monogenic cause of autism and intellectual disability. In fragile X, the loss of the mRNA translational repressor FMRP leads to exaggerated protein synthesis downstream of metabotropic glutamate receptor 5 (mGluR5). We found that mGluR5- and protein synthesis-dependent synaptic plasticity is similarly altered in area CA1 of Mecp2 KO mice. CA1 pyramidal cell-type-specific, genome-wide profiling of ribosome-bound mRNAs was performed in wild-type and Mecp2 KO hippocampal CA1 neurons to reveal the MeCP2-regulated 'translatome'. We found significant overlap between ribosome-bound transcripts overexpressed in the Mecp2 KO and FMRP mRNA targets. These tended to encode long genes that are functionally related to either cytoskeleton organization or the development of neuronal connectivity. In the Fmr1 KO mouse, chronic treatment with mGluR5 negative allosteric modulators (NAMs) has been shown to ameliorate many mutant phenotypes by correcting excessive protein synthesis. In the Mecp2 KO mice we found that mGluR5 NAM treatment significantly reduces the level of overexpressed ribosome-associated transcripts, particularly those that are also FMRP targets. Some Rett phenotypes were also ameliorated by treatment, most notably hippocampal cell size and life span. Together, these results suggest a potential mechanistic link between MeCP2-mediated transcription regulation and mGluR5/FMRP-mediated protein translation regulation through co-regulation of a subset of genes relevant to synaptic functions. Overall design: TRAP-seq analysis of the effect of negative modulator of mGluR5 on the CA1 neurons (marked by Cck-EGFP-L10a) of a mouse model of Rett syndrome
Publication Title
Negative Allosteric Modulation of mGluR5 Partially Corrects Pathophysiology in a Mouse Model of Rett Syndrome.
Sample Metadata Fields
Specimen part, Cell line, Treatment, Subject
View Samples- Mus musculus
- 142 Downloadable Samples
- Illumina HiSeq 4000, Illumina HiSeq 2500
Description
Excessive mRNA translation downstream of group I metabotropic glutamate receptors (mGlu1/5) is a core pathophysiology of fragile X syndrome (FX), however the differentially translating mRNAs that contribute to altered neural function are not known. We used Translating Ribosome Affinity Purification (TRAP) and RNA-seq to identify mistranslating mRNAs in CA1 pyramidal neurons of the FX mouse model (Fmr1-/y) hippocampus, which exhibit exaggerated mGlu1/5-induced long-term synaptic depression (LTD). In these neurons, we find the Chrm4 transcript encoding muscarinic acetylcholine receptor 4 (M4) is excessively translated, and synthesis of M4 downstream of mGlu5 activation is mimicked and occluded. Surprisingly, enhancement rather than inhibition of M4 activity normalizes core phenotypes in the Fmr1-/y, including excessive protein synthesis, exaggerated mGluR-LTD, and audiogenic seizures. These results suggest that not all excessively translated mRNAs in the Fmr1-/y brain are detrimental, and some may be candidates for enhancement to correct pathological changes in the FX brain. Overall design: 6 biological replicates of total hippocampal mRNA (Input) from WT and Fmr1 KO littermate pairs and CA1-TRAP-IP (IP) from the same 6 WT and KO littermate pairs.
Publication Title
Cell-Type-Specific Translation Profiling Reveals a Novel Strategy for Treating Fragile X Syndrome.
Sample Metadata Fields
Sex, Specimen part, Cell line, Subject
View Samples- Mus musculus
- 31 Downloadable Samples
- Illumina HiSeq 2500
Description
Large-scale genome sequencing is poised to provide a substantial increase in the rate of discovery of disease-associated mutations, but the functional interpretation of such mutations remains challenging. Here we show that deletions of a sequence on human chromosome 16 that we term the intestine-critical region (ICR) cause intractable congenital diarrhoea in infants. Reporter assays in transgenic mice show that the ICR contains a regulatory sequence that activates transcription during the development of the gastrointestinal system. Targeted deletion of the ICR in mice caused symptoms that recapitulated the human condition. Transcriptome analysis revealed that an unannotated open reading frame (Percc1) flanks the regulatory sequence, and the expression of this gene was lost in the developing gut of mice that lacked the ICR. Percc1 knockout mice displayed phenotypes similar to those observed on ICR deletion in mice and patients, whereas an ICR-driven Percc1 transgene was sufficient to rescue the phenotypes found in mice that lacked the ICR. Together, our results identify a gene that is critical for intestinal function and underscore the need for targeted in vivo studies to interpret the growing number of clinical genetic findings that do not affect known protein-coding genes. Overall design: Total RNA-seq from dissected regions of the digestive tract, from wild-type and percc1-/- mice.
Publication Title
Noncoding deletions reveal a gene that is critical for intestinal function.
Sample Metadata Fields
Specimen part, Subject
View Samples- Mus musculus
- 159 Downloadable Samples
Illumina MouseRef-8 v2.0 expression beadchip
Description
We investigated the molecular mechanisms of chronic alcohol consumption or lipopolysaccharide insult by gene expression profiling in prefrontal cortex and liver of C57BL/6J mice.
Publication Title
Gene expression in brain and liver produced by three different regimens of alcohol consumption in mice: comparison with immune activation.
Sample Metadata Fields
Age, Specimen part
View Samples- Sus scrofa
- 121 Downloadable Samples
- Affymetrix Porcine Genome Array (porcine)
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
A high protein diet during pregnancy affects hepatic gene expression of energy sensing pathways along ontogenesis in a porcine model.
Sample Metadata Fields
Specimen part
View Samples- Sus scrofa
- 67 Downloadable Samples
- Affymetrix Porcine Genome Array (porcine)
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
Transcriptional response of skeletal muscle to a low-protein gestation diet in porcine offspring accumulates in growth- and cell cycle-regulating pathways.
Sample Metadata Fields
Specimen part
View Samples- Sus scrofa
- 62 Downloadable Samples
- Affymetrix Porcine Genome Array (porcine)
Description
German landrace gilts were fed a high protein diet (HP, 30% CP) throughout their whole pregnancy. Subsequently hepatic transcriptome profiles of the offspring were analysed at prenatal (94 dpc) and postnatal stages (1, 28, 188 dpn)
Publication Title
A high protein diet during pregnancy affects hepatic gene expression of energy sensing pathways along ontogenesis in a porcine model.
Sample Metadata Fields
Specimen part
View Samples- Sus scrofa
- 59 Downloadable Samples
- Affymetrix Porcine Genome Array (porcine)
Description
German landrace gilts were fed an adequate protein diet (AP, 12% CP) throughout their whole pregnancy. Subsequently hepatic transcriptome profiles of the offspring were analysed at prenatal (94 dpc) and postnatal stages (1, 28, 188 dpn).
Publication Title
A high protein diet during pregnancy affects hepatic gene expression of energy sensing pathways along ontogenesis in a porcine model.
Sample Metadata Fields
Specimen part
View Samples