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Autism-linked UBE3A gain-of-function mutation causes interneuron and behavioral phenotypes when inherited maternally or paternally in mice (Bulk RNA-Seq)

ABSTRACT: Autism-linked UBE3A gain-of-function mutation causes interneuron and behavioral phenotypes when inherited maternally or paternally in mice (Bulk RNA-Seq)

PROVIDER: PRJNA832794 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR18957800_1.fastq.gz	Fastqsanger.gz
	SRR18957800_2.fastq.gz	Fastqsanger.gz
	SRR18957801_1.fastq.gz	Fastqsanger.gz
	SRR18957801_2.fastq.gz	Fastqsanger.gz
	SRR18957802_1.fastq.gz	Fastqsanger.gz

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Autism-linked UBE3A gain-of-function mutation causes interneuron and behavioral phenotypes when inherited maternally or paternally in mice (scRNA-Seq)

Project description:The E3 ubiquitin ligase Ube3a is biallelically expressed in mitotic cells, including neural progenitors and glial cells, raising the possibility that UBE3A gain-of-function mutations might cause neurodevelopmental disorders irrespective of parent-of-origin. To test this possibility, we engineered a mouse line that harbors an autism-linked UBE3A-T485A (T508A in mouse) gain-of-function mutation and evaluated phenotypes in animals that inherited the mutant allele paternally, maternally, or from both parents. We found that both paternally and maternally expressed UBE3A-T485A resulted in elevated UBE3A activity in neural progenitors and glial cells where Ube3a is biallelically expressed. Expression of UBE3A-T485A from the maternal allele, but not the paternal one, led to a persistent elevation of UBE3A activity in postmitotic neurons. Maternal, paternal, or biparental inheritance of the mutant allele promoted embryonic expansion of Zcchc12 lineage interneurons which mature into Sst and Calb2 expressing interneurons, and caused a spectrum of behavioral phenotypes that differed by parent-of-origin. Phenotypes were distinct from those observed in Angelman syndrome model mice that harbor a Ube3a maternal loss-of-function allele. Our study shows that the UBE3A-T485A gain-of-function mutation causes distinct neurodevelopmental phenotypes when inherited maternally or paternally. These findings have clinical implications for a growing number of disease-linked UBE3A gain-of-function mutations.

2023-07-03 | GSE201733 | GEO

Autism-linked UBE3A gain-of-function mutation causes interneuron and behavioral phenotypes when inherited maternally or paternally in mice (Bulk RNA-Seq)

2023-07-03 | GSE201731 | GEO

Autism-linked UBE3A gain-of-function mutation causes interneuron and behavioral phenotypes when inherited maternally or paternally in mice

Project description:Autism-linked UBE3A gain-of-function mutation causes interneuron and behavioral phenotypes when inherited maternally or paternally in mice

| PRJNA832791 | ENA

Autism-linked UBE3A gain-of-function mutation causes interneuron and behavioral phenotypes when inherited maternally or paternally in mice (scRNA-Seq)

Project description:Autism-linked UBE3A gain-of-function mutation causes interneuron and behavioral phenotypes when inherited maternally or paternally in mice (scRNA-Seq)

| PRJNA832793 | ENA

Autism-linked UBE3A gain-of-function mutation causes interneuron and behavioral phenotypes when inherited maternally or paternally in mice.

Project description:The E3 ubiquitin ligase Ube3a is biallelically expressed in neural progenitors and glial cells, suggesting that UBE3A gain-of-function mutations might cause neurodevelopmental disorders irrespective of parent of origin. Here, we engineered a mouse line that harbors an autism-linked UBE3AT485A (T503A in mouse) gain-of-function mutation and evaluated phenotypes in animals that inherited the mutant allele paternally, maternally, or from both parents. We find that paternally and maternally expressed UBE3AT503A results in elevated UBE3A activity in neural progenitors and glial cells. Expression of UBE3AT503A from the maternal allele, but not the paternal one, leads to a persistent elevation of UBE3A activity in neurons. Mutant mice display behavioral phenotypes that differ by parent of origin. Expression of UBE3AT503A, irrespective of its parent of origin, promotes transient embryonic expansion of Zcchc12 lineage interneurons. Phenotypes of Ube3aT503A mice are distinct from Angelman syndrome model mice. Our study has clinical implications for a growing number of disease-linked UBE3A gain-of-function mutations.

| S-EPMC10530456 | biostudies-literature

Autism-linked UBE3A gain-of-function mutation causes interneuron and behavioral phenotypes when inherited maternally or paternally in mice

Project description:This SuperSeries is composed of the SubSeries listed below.

2023-07-03 | GSE201734 | GEO

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

Ube3a-ATS characterization with strand-speicific microarray

Project description:This strand-specific array is performed to characterize expression features of Ube3a-ATS, including its imprinting status, its exon-intron structure, its transcriptional initiation and termination site as well as its polyadenylation status. The array contains reverse-complementary probes detecting transcripts from both strands and therefore we are able to pick up signal from both Ube3a sense and antisense. By comparing wild-type with various mutants, and total RNA with polyA RNA, we concluded that Ube3a-ATS is a paternally imprinted gene covering the whole gene body of Ube3a in the antisense orientation. It does not have an obvious exon-intron structure. Its transcription initiates at Snrpn major promoter and terminates ~40kb upstream of Ube3a transcriptional start site. Total RNA from Snrpn-Ube3a maternal deletion mutant (del s-u/+), its wild-type littermate, paternal deletion mutant and its wildtype littermate were analyzed. Mutant mice with S-U maternal deletion and Snrpn promoter paternal deleiton which leads to depletion of Ube3a-ATS (del s-u/0.9 and del s-u/4.8) were also analyzed. polyA RNA was purified from the sample 2 and sample 4. All eight samples were hybridized to the custom 8X60k Agilent CGH array.

2012-05-02 | E-GEOD-29254 | biostudies-arrayexpress

Ube3a-ATS characterization with strand-speicific microarray

2012-05-03 | GSE29254 | GEO

Molecular and behavioral consequences of Ube3a gene overdosage in mice

Project description:Here, we investigated the neurodevelopmental impact of Ube3a gene overdosage using bacterial artificial chromosome-based transgenic mouse models (Ube3aOE) that recapitulate the increases in Ube3a copy number most often observed in Dup15q.Here, we investigated the neurodevelopmental impact of Ube3a gene overdosage using bacterial artificial chromosome-based transgenic mouse models (Ube3aOE) that recapitulate the increases in Ube3a copy number most often observed in Dup15q. Hereto we performed gene expression profiling analysis using data obtained from RNA-seq of cortical and hippocampal tissue from wildtype and Ube3aOE mice

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