Isolated loss of the AUTS2 long isoform, brain-wide or targeted to Calbindin-lineage cells, generates a specific suite of brain, behavioral and molecular pathologies
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PROVIDER: PRJNA966985 | ENA |
REPOSITORIES: ENA
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Project description:Rearrangements within the AUTS2 region are associated with a rare syndromic disorder with intellectual disability, developmental delay and behavioral abnormalities as core features. In addition, smaller regional variants are linked to wide range of neuropsychiatric disorders, underscoring the gene’s essential role in brain development. Like many essential neurodevelopmental genes, AUTS2 is large and complex, generating distinct long (AUTS2-l) and short (AUTS2-s) protein isoforms from alternative promoters. Although evidence suggests unique isoform functions, the contributions of each isoform to specific AUTS2-linked phenotypes have not been clearly resolved. Furthermore, Auts2 is widely expressed across the developing brain, but cell populations most central to disease presentation have not been determined. In this study, we focused on the specific roles of AUTS2-l in brain development, behavior, and postnatal brain gene expression, showing that brain-wide AUTS2-l ablation leads to specific subsets of the recessive pathologies associated with C-terminal mutations that disrupt both isoforms. We identify downstream genes that could explain expressed phenotypes including hundreds of putative direct AUTS2-l target genes. Furthermore, in contrast to C-terminal Auts2 mutations which lead to dominant hypoactivity, AUTS2-l loss-of-function is associated with dominant hyperactivity, a phenotype exhibited by many human patients. Finally, we show that AUTS2-l ablation in Calbindin 1-expressing cell lineages is sufficient to yield learning/memory deficits and hyperactivity with abnormal dentate gyrus granule cell maturation, but not other phenotypic effects. These data provide new clues to in vivo AUTS2-l functions and novel information relevant to genotype-phenotype correlations in the human AUTS2 region.
2023-09-29 | GSE231599 | GEO
Project description:AUTS2 was originally discovered as the gene disrupted by a translocation in human twins with Autism spectrum disorder (ASD), intellectual disability, and epilepsy. Since that initial finding, AUTS2-linked mutations and variants have been associated with a very broad array of neuropsychiatric disorders, suggesting that AUTS2 is required for fundamental steps of neurodevelopment. However, genotype-phenotype correlations in this region are complicated, because most mutations could also involve neighboring genes. Of particular interest in this regard is the nearest downstream neighbor of AUTS2, GALNT17, encoding a brain-expressed N-acetylgalactosaminyltransferase of unknown brain function. Here we describe a mouse (Mus musculus) mutation, T(5G2;8A1)GSO (abbreviated 16Gso), a reciprocal translocation that breaks between Auts2 and Galnt17 and dysregulates both genes. Despite this complex regulatory effect, 16Gso homozygotes model certain human AUTS2-linked phenotypes very well. In addition to abnormalities in growth, craniofacial structure, learning and memory, and behavior, 16Gso homozygotes display distinct pathologies of the cerebellum and hippocampus that are similar to those associated with ASD and other types of neurological disease associated with this genomic region. Analyzing the mutant cerebellar and hippocampal transcriptomes, we identified disturbances in pathways related to neurite and synapse maturation, neurotransmitter signaling, and cellular stress, suggesting possible cellular mechanisms for 16Gso phenotypes. These pathways, coupled with the translocation’s selective effects on Auts2 isoforms and coordinated dysregulation of Galnt17, suggest novel hypotheses regarding the etiology of the human “AUTS2 syndrome” and the wide array of neurodevelopmental disorders linked to variance in this genomic region.
2019-10-18 | GSE132684 | GEO
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:Microglia protect against age-associated brain pathologies
| PRJNA1111815 | ENA
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: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: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. ChIP-seq experiments of PRC1 components, PolII as well as histone modifications were performed either in mouse whole brain or in human 293T-REx lines expressing FLAG/HA-tagged subunits. RNA-seq was performed to analyze the expression profile of mouse whole brain.
2014-12-18 | E-GEOD-60409 | biostudies-arrayexpress
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. mRNA profiles of P1 brain from wild type mice were generated by deep sequencing
2014-12-18 | E-GEOD-60410 | biostudies-arrayexpress
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: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