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

ABSTRACT: 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.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE60409 | GEO | 2014/12/18

SECONDARY ACCESSION(S): PRJNA258289

REPOSITORIES: GEO

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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

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

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

NRF1 Association with AUTS2-Polycomb Mediates Specific Gene Activation in the Brain

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

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

Polycomb repressive complex 1 (PRC1) role in skin epithelium development [ChIP-seq Auts2, Bmi1, Rybp]

Project description:Polycomb repressive complex 1 (PRC1) role in skin epithelium development [ChIP-seq Auts2, Bmi1, Rybp]

| PRJNA446723 | ENA

Polycomb repressive complex 1 (PRC1) role in skin epithelium development [ChIP-seq Auts2, Cbx8, Kdm2b, L3mbtl2]

Project description:Polycomb repressive complex 1 (PRC1) role in skin epithelium development [ChIP-seq Auts2, Cbx8, Kdm2b, L3mbtl2]

| PRJNA447393 | ENA

Polycomb repressive complex 1 (PRC1) role in skin epithelium development [ChIP-seq Auts2, Bmi1, Rybp]

Project description:Polycomb repressive complexes (PRC) 1 and 2 are essential chromatin regulators of cell identity. PRC1, a dominant executer of Polycomb-mediated control, functions as multiple sub-complexes that possess catalytic-dependent H2AK119 mono-ubiquitination (H2AK119ub) and catalytic-independent activities. Here, we show that despite its well-established repressor functions, PRC1 binds to both silent and active genes. Through in vivo loss-of-function studies, we show that global PRC1 function is essential for skin development and stem cell (SC) specification.

2018-03-31 | GSE112450 | GEO

Polycomb repressive complex 1 (PRC1) role in skin epithelium development [ChIP-seq Auts2, Cbx8, Kdm2b, L3mbtl2]

2018-03-31 | GSE112456 | GEO

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