Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

AUTS2 forms a novel complex to recruit CUL4 E3 for BMP inhibition and neural differnetiation

ABSTRACT: Neurodevelopmental disorders (NDD) present a great challenge for medicine due to their complicated etiology and diverse genetic lesions. Although many risk genes have been identified, we know little about their mechanistic impact on NDD pathogenesis, including that of a prominent risk factor, Autism Susceptibility Candidate 2 (AUTS2). Disruptions of AUTS2 have been frequently observed in NDD patients, but it remains unclear how AUTS2 controls the neurodevelopmental program. Our studies investigated the role of AUTS2 in neuronal differentiation and discovered that AUTS2, together with WDR68 and SKI, form a novel protein complex (AWS) specifically in neuronal progenitors and promotes neuronal differentiation through inhibiting BMP signaling. Genomic and biochemical analyses demonstrated that the AWS complex achieves this effect through the recruitment of the CUL4 E3 ubiquitin ligase complex to mediate poly-ubiquitination and subsequent proteasomal degradation of phosphorylated SMAD1/5/9. Using primary cortical neurons from Auts2 deficient mice, we also observed aberrant BMP signaling and dysregulated expression of neuronal genes, indicating that the AWS-CUL4-BMP axis plays a role in regulating neuronal lineage specification in vivo. Our findings uncover a sophisticated cellular signaling network, mobilized by a prominent NDD risk factor, presenting multiple potential therapeutic targets for NDD.

ORGANISM(S): Mus musculus

PROVIDER: GSE178746 | GEO | 2022/12/01

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

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. mRNA profiles of P1 brain from wild type mice were generated by deep sequencing

2014-12-18 | E-GEOD-60410 | biostudies-arrayexpress

Dysregulation of NRSF/REST via EHMT1 is associated with psychiatric disorders

Project description:Genetic evidence indicates disrupted epigenetic regulation as a major risk factor for psychiatric disorders, but the molecular mechanisms that drive this association are undetermined. EHMT1 is an epigenetic repressor that is causal for Kleefstra Syndrome (KS), a neurodevelopmental disorder (NDD) leading to ID, and is associated with schizophrenia. Here, we show that reduced EHMT1 activity decreases NRSF/REST protein leading to abnormal neuronal gene expression and progression of neurodevelopment in human iPSC. We further show that EHMT1 regulates NRSF/REST indirectly via repression of miRNA leading to aberrant neuronal gene regulation and neurodevelopment timing. Expression of a NRSF/REST mRNA that lacks the miRNA-binding sites restores neuronal gene regulation to EHMT1 deficient cells. Importantly, the EHMT1-regulated miRNA gene set with elevated expression is enriched for NRSF/REST regulators with an association for ID and schizophrenia. This reveals a molecular interaction between H3K9 dimethylation and NSRF/REST contributing to the aetiology of psychiatric disorders.

2023-05-01 | E-MTAB-10480 | biostudies-arrayexpress

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

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

2014-12-18 | GSE60410 | GEO

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

2014-12-18 | GSE60409 | 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

WDR68 is essential for the PRC1-AUTS2 complex activating role and for stem cell differentiation

Project description:Recent studies on Polycomb repressive complexes (PRC) reveal a surprising role in transcriptional activation, yet the underlying mechanism remains poorly understood. We previously identified a type 1 PRC (PRC1) that contains Autism Susceptibility Candidate 2 (AUTS2), which positively regulates transcription of neuronal genes. However, the mechanism by which the PRC1-AUTS2 complex influences neurodevelopment is unclear. Here we demonstrate that WDR68 is not only an integral component of the PRC1-AUTS2 complex, it is required for PRC1-AUTS2-mediated transcription activation. Furthermore, deletion of Wdr68 in mouse embryonic stem cells leads to defects in neuronal differentiation without affecting self-renewal. Through transcriptomic analysis, we found that many genes responsible for neuronal differentiation are down-regulated in Wdr68 deficient neural progenitors. These genes include several that are targeted by the PRC1-AUTS2 complex. In summary, our studies uncovered a previously unknown but essential component of the active PRC1 complex and evidence of its role in regulating the expression of genes that may be important for neuronal differentiation.

2020-07-29 | GSE115576 | GEO

comparison_col0vsskp2-Functional analysis of the SKP2 and CUL4 proteins

Project description:rs04-04_skp2_cul4 - comparison_col0vsskp2 - Antisense and mutants of the SKP2 and CUL4 genes are compared to the Wt in order to identify the genes controlled by those SCF proteins. - Comparison Col0 versus skp2

2012-03-27 | GSE36651 | GEO

comparison_col0vsskp2-Functional analysis of the SKP2 and CUL4 proteins

2012-03-26 | E-GEOD-36651 | biostudies-arrayexpress

comparison_cul4_as_light-Functional analysis of the SKP2 and CUL4 proteins

Project description:rs04-04_skp2_cul4 - comparison_cul4_as_light - Antisense and mutants of the SKP2 and CUL4 genes are compared to the Wt in order to identify the genes controlled by those SCF proteins. - The seeds have been sown every two days on MS 255 (Duschefa) without 1% sugar. These plates stayed 6 days in the dark at 4 Â°C. Then they were transfered to the light for 6 more days. 4 dye-swap - gene knock out, normal vs antisense mutant comparison

2012-03-26 | E-GEOD-36655 | biostudies-arrayexpress

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data