An Auts2-Containing RNA-Binding Complex Regulates Transcript Expression in Developing Cerebral Cortex
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA449095 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR6956200_1.fastq.gz | Fastqsanger.gz | |||
| SRR6956200_2.fastq.gz | Fastqsanger.gz | |||
| SRR6956210_1.fastq.gz | Fastqsanger.gz | |||
| SRR6956210_2.fastq.gz | Fastqsanger.gz | |||
| SRR6956201_1.fastq.gz | Fastqsanger.gz |
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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
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
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
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 | GSE255183 | GEO
Project description:Polycomb group (PcG) proteins are evolutionarily conserved chromatin-modifying factors that regulate gene expression to control tissue development. We previously discovered an AUTS2?Polycomb complex activates gene expression by recruiting Casein kinase 2 (CK2) and P300. But the mechanisms underlying the recruitment of AUTS2-PRC1 to chromatin and the physiological relevance of AUTS2-P300 interaction during neurodevelopment remain unknown. Here, we report that the transcription factor Nuclear Respiratory Factor 1 (NRF1) physically interacts with AUTS2 and overlaps with AUTS2 on chromatin binding. In a functional study combined with the single cell RNA-seq approach, we demonstrate that NRF1 is required for AUTS2 recruitment to chromatin, ncPRC1 associated active transcription in motor neuron and thereby modulates multipotent progenitors to motor neuron differentiation. Moreover, we discover that mutations within AUTS2 HX repeat region, which associate with RSTS phenotype disrupt AUTS2-P300 interaction and AUTS2 mediated transcriptional activation. Together, these findings reveal the underlying mechanism by which the AUTS2-containing ncPRC1 complex is recruited and activates transcription and mutations in the AUTS2 HX repeat region exert a dominant negative effect on AUTS2-P300 mediated transcriptional activation in RSTS.
2021-10-11 | GSE161808 | GEO
Project description:The cerebral cortex underwent a rapid expansion and complexification during recent primate evolution, but the underlying developmental mechanisms remain essentially unknown. In order to uncover genetic networks underlying the development of the human cerebral cortex, we profiled the transcriptome of human fetal cortical domains containing language areas of Broca and Wernicke, as well as associative areas. We thus identified hundreds of genes displaying differential expression between the two areas or between distinct temporal stages. A subset of these genes was further validated by qRTPCR and in situ hybridization, revealing novel patterns of area and layer-specific expression throughout the developing cortex at midgestation, a critical period of cortical patterning. Computational genomic analyses revealed that the proportion of genes located close to evolutionarily accelerated regions was far more abundant among the genes differentially expressed between the two cortical areas examined, but not among those differentially expressed between different stages of development. In silico screening enabled to identify accelerated regions displaying increased turnover of change in transcription factor binding sites, which were enriched among those closer to genes differentially expressed between cortical areas. Overall our work points to the identification of cortical genes that display a unique combination of patterns of evolution and expression, which may constitute an important part of the genetic framework underlying human-specific neural traits and diseases. We determined gene expression patterns in cortical domains that contain areas thought to have undergone significant divergence during primate evolution, including language areas of Broca and Wernicke, as well as association areas of the frontal and parieto-temporal cortex in the right and left sides of human fetal brains at 17 and 19 gestional weeks.
2011-06-01 | E-GEOD-21858 | biostudies-arrayexpress
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
Project description:The cerebral cortex underwent a rapid expansion and complexification during recent primate evolution, but the underlying developmental mechanisms remain essentially unknown. In order to uncover genetic networks underlying the development of the human cerebral cortex, we profiled the transcriptome of human fetal cortical domains containing language areas of Broca and Wernicke, as well as associative areas. We thus identified hundreds of genes displaying differential expression between the two areas or between distinct temporal stages. A subset of these genes was further validated by qRTPCR and in situ hybridization, revealing novel patterns of area and layer-specific expression throughout the developing cortex at midgestation, a critical period of cortical patterning. Computational genomic analyses revealed that the proportion of genes located close to evolutionarily accelerated regions was far more abundant among the genes differentially expressed between the two cortical areas examined, but not among those differentially expressed between different stages of development. In silico screening enabled to identify accelerated regions displaying increased turnover of change in transcription factor binding sites, which were enriched among those closer to genes differentially expressed between cortical areas. Overall our work points to the identification of cortical genes that display a unique combination of patterns of evolution and expression, which may constitute an important part of the genetic framework underlying human-specific neural traits and diseases.
2011-06-01 | GSE21858 | GEO
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 | GSE60409 | GEO
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