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Sex-biasing influence of autism-associated Ube3a gene overdosage at connectomic, behavioral and transcriptomic levels

ABSTRACT: Sex-biasing influence of autism-associated Ube3a gene overdosage at connectomic, behavioral and transcriptomic levels

PROVIDER: PRJNA898989 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR22214200_1.fastq.gz	Fastqsanger.gz
	SRR22214200_2.fastq.gz	Fastqsanger.gz
	SRR22214201_1.fastq.gz	Fastqsanger.gz
	SRR22214201_2.fastq.gz	Fastqsanger.gz
	SRR22214202_1.fastq.gz	Fastqsanger.gz

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Sex-biasing influence of autism-associated Ube3a gene overdosage at connectomic, behavioral and transcriptomic levels

Project description:We tested the hypothesis that increase dosage of Ube3a may exert its influence on transcriptomic organization in a sex-biased manner

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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.

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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)

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Excessive UBE3A dosage impairs fine-tuning of retinoid acid signaling in autism spectrum disorders

Project description:The autism spectrum disorders (ASD) are a collection of disorders with heterogeneous etiology, exhibiting common traits including impaired social interactions and communications, repetitive behaviors. 15q11-q13 copy number variations (CNV) were found in 1-3% of ASD cases; of which the detailed mechanism of the major contributor UBE3A gene acted still remained elusive. Here we identified a key enzyme in RA synthesis, negatively regulated in ubiquitination-dependent mode promoted by UBE3A. Our data provide evidences linking UBE3A hyperactivity with ASD phenotypes, with implications for understanding ASD etiology and providing potential interventions in ASD clinical therapy.

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Sex-biasing influence of autism-associated <i>Ube3a</i> gene overdosage at connectomic, behavioral, and transcriptomic levels.

Project description:Genomic mechanisms enhancing risk in males may contribute to sex bias in autism. The ubiquitin protein ligase E3A gene (Ube3a) affects cellular homeostasis via control of protein turnover and by acting as transcriptional coactivator with steroid hormone receptors. Overdosage of Ube3a via duplication or triplication of chromosomal region 15q11-13 causes 1 to 2% of autistic cases. Here, we test the hypothesis that increased dosage of Ube3a may influence autism-relevant phenotypes in a sex-biased manner. We show that mice with extra copies of Ube3a exhibit sex-biasing effects on brain connectomics and autism-relevant behaviors. These effects are associated with transcriptional dysregulation of autism-associated genes, as well as genes differentially expressed in 15q duplication and in autistic people. Increased Ube3a dosage also affects expression of genes on the X chromosome, genes influenced by sex steroid hormone, and genes sex-differentially regulated by transcription factors. These results suggest that Ube3a overdosage can contribute to sex bias in neurodevelopmental conditions via influence on sex-differential mechanisms.

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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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Molecular and behavioral consequences of Ube3a gene overdosage in mice

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

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UBE3A reinstatement restores behavior and proteome in an Angelman syndrome mouse model of imprinting defects

Project description:Angelman Syndrome (AS) is a severe neurodevelopmental disorder with only symptomatic treatment currently available. Besides mutations within the UBE3A gene, AS is caused by deletions, imprinting center defects (mICD) or uniparental disomy of chromosome 15 (UPD). Current mouse models are Ube3a-centric and do not address expression changes of other 15q11-q13 genes on AS pathophysiology. Here, we studied a mouse line that harbors a mutation affecting the AS-PWS imprinting center, hence modeling mICD/UPD AS subtypes. mICD mice showed significant reduction in UBE3A protein, bi-allelic expression of Ube3a-ATS and Mkrn3-Snord115 gene cluster, leading to robust AS behavioral deficits and proteome alterations similar to Ube3aKO mice. Genetic UBE3A overexpression in mICD mice, mimicking therapeutic strategies that effectively activate the biallelic silenced Ube3a gene, resulted in a complete rescue of all behavioral and proteome alterations. Subsequently, treatment with an antisense oligonucleotide (ASO) to directly activate the biallelic silenced Ube3a gene in mICD mice also resulted in efficient reinstatement of UBE3A, alongside a partial rescue of behavioral phenotypes. Taken together, these findings demonstrate that UBE3A loss is the primary factor underlying AS phenotypes in the mICD/UPD mouse model, and also corroborate that UBE3A reinstatement is an attractive therapeutic strategy for mICD/UPD AS individuals.

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Hyperactive UBE3A Variants Cause Neomorphic Neurodevelopmental Phenotypes

Project description:Mutations in the E3 ubiquitin ligase UBE3A that cause enzymatic gain-of-function result in heterogeneous disease phenotypes in humans which differ from classic Angelman syndrome. We describe two affected siblings who possess an inherited UBE3AL734S variant that causes a strong gain in UBE3A activity. Unlike previously described cases, these individuals exhibited borderline microcephaly, suggesting the extent of UBE3A gain-of-function can produce neomorphic phenotypes. Here, we characterize a mouse model harboring a strong gain of function variant (Ube3aQ606E) which elevates UBE3A activity 388% above wild type (WT) enzyme levels. We conduct extensive behavioral phenotyping to show that Ube3amQ606E mutants show motor deficits, hypoactivity, and reduced stereotypic behaviors. Brain weights and MRI analysis revealed global microcephaly with a postnatal onset. Proteomic analysis performed on neonatal cortex revealed perturbations in several key proteins and pathways linked to neurodevelopmental disease. Finally, we show that microcephaly is not caused by increased apoptotic cell death. Together, our results provide strong evidence that the type and severity of disease phenotypes depend on the causative UBE3A gain of function mutation and provide new insights into the phenotypic heterogeneity observed in individuals with UBE3A gain of function variants.

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