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Disease-related AUTS2 disruption causes an imbalance of neuronal/glial lineage specification through the WNT/β-catenin pathway (RNA-Seq).

ABSTRACT: Disease-related AUTS2 disruption causes an imbalance of neuronal/glial lineage specification through the WNT/β-catenin pathway (RNA-Seq).

PROVIDER: PRJNA1073898 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR27890419_1.fastq.gz	Fastqsanger.gz
	SRR27890419_2.fastq.gz	Fastqsanger.gz
	SRR27890420_1.fastq.gz	Fastqsanger.gz
	SRR27890420_2.fastq.gz	Fastqsanger.gz
	SRR27890421_1.fastq.gz	Fastqsanger.gz

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Project description:Individuals with disruptions in the Autism Susceptibility Candidate 2 (AUTS2) gene frequently exhibit symptoms like intellectual disability, microcephaly, growth retardation, and distinct skeletal and facial differences. The role of AUTS2 in neurodevelopment has been explored using animal models and in vitro embryonic stem cell models. However, the precise molecular mechanisms through which AUTS2 influences neurodevelopment, particularly in humans, are not thoroughly understood. To address this, our study employs a 3D human organoid culture system, in combination with genetic, genomic, cellular, and molecular approaches, to investigate how AUTS2 impacts neurodevelopment through cellular signaling pathways. We used CRISPR/Cas9 technology to create AUTS2-deficient human embryonic stem cells (hESCs), replicating a 190kb genetic deletion observed in a patient. These cells were then differentiated into cerebral organoids. Our single-cell RNA sequencing (scRNA-seq) analysis of these organoids indicates that the absence of AUTS2 results in a significant reduction in neuron-related cells and an increase in choroid plexus (ChP) epithelial cells. Notably, our research reveals that AUTS2 negatively regulates the Wnt/β-catenin signaling pathway, evidenced by the observed overactivation of this pathway in AUTS2-deficient organoids as well as in a luciferase reporter cell line with AUTS2 deletion. Importantly, treating the AUTS2-deficient cerebral organoids with a Wnt inhibitor ameliorated the abnormalities in neuronal differentiation. This study offers new insights into the role of AUTS2 in neurodevelopment and suggests new potential targeted therapies for NDDs.

2024-09-27 | GSE255184 | GEO

2024-09-27 | GSE255183 | GEO

Project description:Disease-related AUTS2 disruption causes an imbalance of neuronal/glial lineage specification through the WNT/β-catenin pathway

| PRJNA1073901 | ENA

Project description:Disease-related AUTS2 disruption causes an imbalance of neuronal/glial lineage specification through the WNT/β-catenin pathway (scRNA-Seq).

| PRJNA1073913 | ENA

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

2024-09-27 | GSE255185 | GEO

AUTS2 project

Project description:This SuperSeries is composed of the following subset Series: GSE36950: SNP array for CNV calling AUTS2 project [Affymetrix] GSE37141: Oligo array for CNV calling AUTS2 project [Agilent] GSE37142: SNP array for CNV calling AUTS2 project [Illumina] GSE37654: Oligo array for calling CNV's for AUTS2 project [NimbleGen] GSE37656: Oligo array for CNV calling AUTS2 project [Bluegnome] Refer to individual Series

2012-07-11 | E-GEOD-37657 | biostudies-arrayexpress

RNA-seq analysis dataset: Hippocampal tissues from Emx1-Cre;Auts2-flox/flox and Auts2-flox/flox mice at P14

Project description:Previous studies have revealed that AUTS2 regulates cytoskeletal organization as well as gene expression during prenatal brain development. Its involvement in controlling synapses, however, remains unclear. Here, we report the increased dendritic spine formation in Auts2 mutant mice as well as the primary cultured neurons from Auts2 mutant mice. To investigate the involvement of AUTS2 function in the regulation of gene expression, we performed transcriptome analysis. RNA-seq on total RNA from the hippocampal tissues of Emx1Cre/+;Auts2flox/flox homozygous conditional KO mice at P14 reveals changes in gene associated with brain development including synapse formation. These results suggest that AUTS2 regulates the expression of genes that are related to synapse formation/function, and some of which may be involved in spine number restriction. Aberrant expression of such synaptic genes may cause synaptic dysfunction in patients with AUTS2 mutations.

2020-06-17 | GSE134712 | GEO

An Auts2-Containing RNA-Binding Complex Regulates Transcript Expression in Developing Cerebral Cortex

Project description:Molecular functions of the intellectual disability syndrome gene AUTS2 remain uncertain. Two mechanisms of Auts2 function have been proposed. One study found that Auts2 modifies Polycomb repressive complex 1 (PRC1) to activate transcription of target neurodevelopmental genes by recruiting EP300, a histone acetyltransferase. A second study found that cytoplasmic AUTS2 regulates cytoskeletal assembly through PREX1 to promote neurite outgrowth and migration. To further investigate Auts2 functions, we screened for AUTS2 interactors in cerebral cortex, and profiled changes of transcript expression in the developing cortex of Auts2 conditional mutant mice. AUTS2 immunoprecipitation experiments identified interactions with proteins involved in pre-mRNA processing, and mRNAs, including those encoding EP300 and PREX1, both bound by AUTS2-containing complexes and dysregulated in Auts2 mutant cortex. We propose that AUTS2 interacts with an RNA-binding complex that directly targets transcripts encoding Auts2 effectors. This mechanism provides a unifying model that accounts for previously disparate hypotheses of AUTS2 functions.

2021-05-21 | GSE112792 | GEO

AUTS2 confers transcriptional activation to PRC1 in the CNS (RNA-Seq)

Project description:Naturally occurring variations of Polycomb Repressive Complex 1 (PRC1) comprise a core assembly of Polycomb group proteins and additional factors that include, surprisingly, Autism Susceptibility Candidate 2 (AUTS2). While AUTS2 is often disrupted in patients with neuronal disorders, the underlying mechanism is unclear. We investigated the role of AUTS2 as part of a previously identified PRC1 complex (PRC1-AUTS2), and in the context of neurodevelopment. In contrast to the canonical role of PRC1 in gene repression, PRC1-AUTS2 activates transcription. Biochemical studies demonstrate that the CK2 component of PRC1-AUTS2 thwarts PRC1 repressive activity and AUTS2-mediated recruitment of P300 leads to gene activation. ChIP-seq of AUTS2 shows that it regulates neuronal gene expression through promoter association. Conditional CNS targeting of Auts2 in a mouse model leads to various developmental defects. These findings reveal a natural means of subverting PRC1 activity, linking key epigenetic modulators with neuronal functions and diseases.

2014-12-18 | GSE60410 | GEO

AUTS2 confers transcriptional activation to PRC1 in the CNS (ChIP-Seq)

2014-12-18 | GSE60409 | GEO