Ontology highlight
ABSTRACT:
PROVIDER: PRJNA712999 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR13922100.fastq.gz | Fastqsanger.gz | |||
| SRR13922101.fastq.gz | Fastqsanger.gz | |||
| SRR13922018.fastq.gz | Fastqsanger.gz | |||
| SRR13922019_1.fastq.gz | Fastqsanger.gz | |||
| SRR13922019_2.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 148 |
Similar Datasets
Project description:Angelman syndrome (AS) is a severe neurodevelopmental disorder caused by
mutations that effect expression of the maternal UBE3A allele, which encodes the
ubiquitin protein ligase E3A (UBE3A). Although several potential UBE3A targets have
been identified, our understanding of relevant disease targets is very limited, and
validation in patient-derived cells is lacking. We established human iPSC (hiPSC)
control and AS patient-derived neuronal models and demonstrate specific and
reciprocal modulation of UBE3A using anti-sense oligonucleotides (ASOs). Through
unbiased proteomic analysis we identified proteins whose abundance were directly affected by manipulating UBE3A levels, including the novel human specific PEG10
protein, a secreted retrotransposon derived GAG domain-containing protein. PEG10
protein, but not RNA, was elevated in AS hiPSC-derived neurons as well as in postmortem
AS brain tissue, and we showed that its upregulation in patient-derived cells is
dependent on both UBE3A and normal proteasome function. Functional analysis
revealed that PEG10 binds both RNA and ataxia associated proteins, ATXN2 and
ATXN10. PEG10 localizes to stress granules and is secreted in extracellular vesicles,
where it regulates vesicle content. AS patient-derived neurons in which either UBE3A
was reinstated or PEG10 was reduced, showed a striking similarity in transcriptome
changes. In addition, overexpression of PEG10 during mouse brain development
affected the migration of the PEG10-overexpressing neurons, suggesting that PEG10
overexpression can affect neuronal function at a critical time during brain development.
Taken together these findings imply that PEG10 is a novel secreted UBE3A target,
and is involved in AS pathophysiology.
2021-06-18 | MSV000087654 | MassIVE
Project description:Angelman syndrome is caused by loss of funtional ubiquitin E3 ligase UBE3A and results in severe deley in cognitive and motor development. In neurons, UBE3A locates to the synapse and to the nucleus. Loss of nuclear UBE3A results in development of Angelman syndrome like symptoms in mice. UBE3A can function as transcriptional coactivator of steroid hormone receptors, but the entire function of UBE3A in the nucleus is still not clear. So we wanted to study differences in the transcriptome in neurons differentiated from iPSCs that were derived from patients with Angleman syndrome and normal controls.
2020-12-31 | GSE146640 | GEO
Project description:Angelman syndrome (AS) is a neurogenetic developmental disorder that results from the loss of E3 ubiquitin ligase UBE3A due to mutations in or deletions of the maternally inherited UBE3A allele. While mouse models of AS have implicated abnormal synaptic signaling and plasticity underlying behavioral dysfunction, how the loss of UBE3A contributes to hyperactivity of neuronal networks seen in AS patients remains unclear. Here, by utilizing human induced neurons and 3D cortical organoids derived from AS patient iPSCs and CRISPR-Cas9 mediated UBE3A KO hESCs, we uncovered a novel role of UBE3A in suppressing neuronal hyperexcitability via ubiquitin-mediated degradation of BK channels. More importantly, augmented BK channel activity in neurons manifested as increased intrinsic excitability of neurons and network level bursting and synchronization, which can be pharmacologically normalized by BK antagonists. Our study has illustrated the utility of modeling neurological diseases with human neural cells, and our results have provided new insights into underlying pathophysiological mechanisms and potential therapeutic strategy in Angelman syndrome.
2020-08-18 | GSE120225 | GEO
Project description:UBE3A encodes a E3 ubiquitin ligase whose loss from the maternal allele causes the neurodevelopmental disorder Angelman syndrome. Previous studies of UBE3A function have not examined full Ube3a deletion in mouse, the complexity of imprinted gene networks in brain, nor the molecular basis of systems-level cognitive dysfunctions in Angelman syndrome. We therefore utilized a systems biology approach to elucidate how UBE3A loss impacts the early postnatal brain in a novel CRISPR/Cas9 engineered rat Angelman model of a complete Ube3a deletion. Strand-specific transcriptome analysis of offspring from maternally or paternally inherited Ube3a deletions revealed the expected parental expression patterns of Ube3a sense and antisense transcripts by postnatal day 2 (P2) in hypothalamus and day 9 (P9) in cortex, compared to wild-type littermates. The dependency of genome-wide effects on parent-of-origin, Ube3a genotype, and time (P2, P9) was investigated through transcriptome (RNA-seq of cortex and hypothalamus) and methylome (whole genome bisulfite sequencing of hypothalamus). Weighted gene co-expression and co-methylation network analyses identified co-regulated networks in maternally inherited Ube3a deletion offspring enriched in postnatal developmental processes including Wnt signaling, synaptic regulation, neuronal and glial functions, epigenetic regulation, ubiquitin, circadian entrainment, and splicing. Furthermore, we showed that loss of the paternal Ube3a antisense transcript resulted in both unique and overlapping dysregulated gene pathways with maternal loss, predominantly at the level of differential methylation. Together, these results provide a holistic examination of the molecular impacts of UBE3A loss in brain, supporting the existence of interactive epigenetic networks between maternal and paternal transcripts at the Ube3a locus.
2020-03-01 | GSE137217 | GEO
Project description:The goal of this study was to determine transcriptional changes in HEK293 cells upon overexpression of various forms of Paternally Expressed Gene 10, or PEG10. Cells were transfected either with control, or with PEG10 gag, gag-pol, or isolated NC fragment constructs and RNA isolated for RNA-Seq analysis.
2023-03-29 | GSE227789 | GEO
Project description:Peg10 (paternally expressed gene 10) is an imprinted gene that is essential for placental development (1). It is thought to derive from a Ty3-gyspy LTR (long terminal repeat) retrotransposon and retains Gag and Pol-like domains (2). Here we show that the Gag domain of PEG10 can promote vesicle budding similar to the HIV p24 Gag protein. Expressed in a subset of mouse endocrine organs in addition to the placenta, PEG10 was identified as a substrate of the deubiquitinating enzyme USP9X. Consistent with PEG10 having a critical role in placental development, PEG10-deficient trophoblast stem cells (TSCs) exhibited impaired differentiation into placental lineages. PEG10 expressed in wild-type, differentiating TSCs was bound to many cellular RNAs including Hbegf (Heparin-binding EGF-like growth factor), which is known to play an important role in placentation (3). Expression of Hbegf was reduced in PEG10-deficient TSCs suggesting that PEG10 might bind to and stabilize RNAs that are critical for normal placental development.
2018-12-14 | MSV000083229 | MassIVE
Project description:Angelman syndrome is a neurodevelopmental disorder caused by (epi)genetic lesions of maternal UBE3A. Research has focused largely on the role of UBE3A in neurons due to its imprinting in that cell type. Yet, evidence suggests there may be broader neurodevelopmental impacts of UBE3A dysregulation. Human cerebral organoids can investigate these understudied aspects of UBE3A as they recapitulate diverse cell types of the developing human brain. We performed single-cell RNA-sequencing on organoids to reveal the effects of UBE3A disruption on cell type-specific transcriptomic alterations and compositions. In the absence of UBE3A, progenitor proliferation and structures were disrupted while organoid composition shifted away from proliferative cell types. We observed impacts on non-neuronal cells including choroid plexus enrichment. Furthermore, EMX1+ cortical progenitors were negatively impacted, disrupting corticogenesis, and potentially delaying neuron maturation. This work reveals novel impacts of UBE3A on understudied cell types and related neurodevelopmental processes and elucidates potential new therapeutic targets.
2024-03-13 | GSE253230 | GEO
Project description:Ubiquitin-protein ligase E3A (UBE3A) has dual functions as a E3 ubiquitin-protein ligase and coactivator of nuclear hormone receptors. Mutations or deletions of the maternally inherited UBE3A gene cause Angelman syndrome. Here, we performed transcriptome profiling in the hippocampus of Ube3am+/p+ and Ube3am-/p+ mice, and determined that the expression of the retinoic acid (RA) signalling pathway was downregulated in Ube3a-deficient mice compared to WT mice. Furthermore, we demonstrated that UBE3A directly interacts with RARα and may function as a coactivator of the nuclear receptor RARα to participate in the regulation of gene expression. Loss of UBE3A expression caused the downregulation of the expression of RA-related genes, including Erbb4, Dpysl3, Calb1, Pten and Arhgap5 in Ube3am-/p+ mice brain tissues. This work revealed a new role for UBE3A in regulating retinoic acid (RA) signalling downstream genes and hopefully to shed light on the potential drug target of AS.
2021-03-15 | GSE168889 | GEO
Project description:Amyotrophic Lateral Sclerosis (ALS) is a rare neurodegenerative disease characterized by motor neuron dysfunction and loss, leading to progressive paralysis and death. A portion of ALS cases is caused by mutation of the proteasome shuttle factor Ubiquilin 2 (UBQLN2), but the molecular pathway leading from UBQLN2 dysfunction to neurodegenerative disease remains unclear. Here, we demonstrate a major function of UBQLN2 in regulating activity of the domesticated gag-pol retrotransposon ‘paternally expressed gene 10’ (PEG10) in human cells and tissues. UBQLN2 exclusively facilitates degradation of the frameshifted gag-pol form of PEG10 through recognition of a unique polyproline repeat. In cells, the PEG10 gag-pol protein cleaves itself in a mechanism reminiscent of retrotransposon self-processing to generate a liberated ‘nucleocapsid’ fragment, which uniquely localizes to the nucleus. Overexpression of the nucleocapsid fragment upregulates transcription of neuronal genes involved in axon remodeling, which were also affected in sporadic ALS (sALS) patient tissues. Finally, proteomics of spinal cords from ALS patients revealed that PEG10 gag-pol is significantly elevated in disease compared to healthy controls. These findings implicate the retrotransposon-like activity of PEG10 as a contributing mechanism in ALS through regulation of neuronal gene expression, and restraint of PEG10 as a primary function of UBQLN2.
2023-03-24 | PXD031964 | Pride
Project description:Angelman syndrome (AS) is a severe neurodevelopmental disorder caused by maternal mutation and paternal imprinting of the gene encoding UBE3A, an E3 ubiquitin ligase. Although several potential target proteins of UBE3A have been reported, how these proteins regulate neuronal development remains unclear. We performed a large-scale quantitative proteomic analysis using stable-isotope labeling of amino acids in mammals (SILAM) on mice with maternal Ube3a mutation.
2018-12-15 | MSV000083239 | MassIVE