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Imprinting effects of UBE3A loss on synaptic gene networks and Wnt signaling pathways

ABSTRACT: Imprinting effects of UBE3A loss on synaptic gene networks and Wnt signaling pathways

PROVIDER: PRJNA564819 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR10096226_1.fastq.gz	Fastqsanger.gz
	SRR10096226_2.fastq.gz	Fastqsanger.gz
	SRR10096227_1.fastq.gz	Fastqsanger.gz
	SRR10096227_2.fastq.gz	Fastqsanger.gz
	SRR10096228_1.fastq.gz	Fastqsanger.gz

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Imprinting effects of UBE3A loss on synaptic gene networks and Wnt signaling pathways

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

Imprinting effects of UBE3A loss on synaptic gene networks and Wnt signaling pathways.

Project description:Ubiquitin E3 ligase 3A (UBE3A) encodes an E3 ubiquitin ligase whose loss from the maternal allele causes the neurodevelopmental disorder Angelman syndrome (AS). 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 AS. 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 and P9) was investigated through transcriptome (RNA sequencing 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.

| S-EPMC7275372 | biostudies-literature

A bipartite boundary element restricts UBE3A imprinting to mature neurons

Project description:CTCF binding and three-dimensional chromatin interactions (4C-seq) in the region of human chromosome 15 associated with imprinting of UBE3A

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Networks of cultured iPSC-derived neurons reveal the human synaptic activity-regulated adaptive gene program

Project description:We studied the synaptic activity-regulated gene expression response in the human genetic background using cultured human iPSC-derived (hiPSCd) neuronal networks and networks of hiPSCd neurons mixed with mouse primary neurons. Our results confirm that genetic changes affect the synaptic activity-regulated gene program, proposing a functional mechanism how they have driven evolution of human cognitive abilities.

2017-01-03 | GSE88773 | GEO

A bipartite boundary element restricts UBE3A imprinting to mature neurons

Project description:A bipartite boundary element restricts UBE3A imprinting to mature neurons

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Imprinting RNAseq

Project description:Imprinting RNAseq

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Channelopathy pathogenesis in a human neural cell model of Angelman Syndrome

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

HAP1 is an in vivo UBE3A Target that Augments Autophagy in a Mouse Model of Angelman Syndrome

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

Mouse preimplantation imprinting

Project description:Mouse preimplantation imprinting

| PRJNA638349 | ENA

MLID imprinting disorders

Project description:MLID imprinting disorders

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