Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Widespread RNA editing dysregulation in Autism Spectrum Disorders [RNA-Seq]

ABSTRACT: Autism spectrum disorder (ASD) is a neurodevelopmental disease with complex heterogeneity and aberrations in multiple levels of neurobiology. Recently, our understanding of the molecular abnormalities in ASD has been greatly expanded through transcriptomic analyses of postmortem brains. However, a crucial molecular pathway involved in synaptic development, RNA editing, has not yet been studied on a genome-wide scale. Here we profiled the global patterns of adenosine-to-inosine (A-to-I) editing in a large cohort of ASD cortices and cerebella. Strikingly, we observed a global bias of hypoediting in ASD brains, common to different brain regions and involving many genes with critical neurological function. The large-scale RNA editing changes allowed us to reveal novel insights of RNA editing regulation. Through genome-wide protein-RNA binding analyses and detailed molecular assays, we show that the Fragile X proteins, FMRP and FXR1P, interact with ADAR protens and modulate A-to-I editing. Furthermore, we observed convergent patterns of RNA editing alterations between ASD and Fragile X syndrome, thus establishing RNA editing as a novel molecular link underlying these two highly related diseases. Our findings support a role for RNA editing dysregulation in ASD pathophysiology and highlight novel mechanisms for RNA editing regulation.

ORGANISM(S): Homo sapiens

PROVIDER: GSE107867 | GEO | 2018/12/14

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Widespread RNA editing dysregulation in Autism Spectrum Disorders [eCLIP-seq]

Project description:Autism spectrum disorder (ASD) is a neurodevelopmental disease with complex heterogeneity and aberrations in multiple levels of neurobiology. Recently, our understanding of the molecular abnormalities in ASD has been greatly expanded through transcriptomic analyses of postmortem brains. However, a crucial molecular pathway involved in synaptic development, RNA editing, has not yet been studied on a genome-wide scale. Here we profiled the global patterns of adenosine-to-inosine (A-to-I) editing in a large cohort of ASD cortices and cerebella. Strikingly, we observed a global bias of hypoediting in ASD brains, common to different brain regions and involving many genes with critical neurological function. The large-scale RNA editing changes allowed us to reveal novel insights of RNA editing regulation. Through genome-wide protein-RNA binding analyses and detailed molecular assays, we show that the Fragile X proteins, FMRP and FXR1P, interact with ADAR protens and modulate A-to-I editing. Furthermore, we observed convergent patterns of RNA editing alterations between ASD and Fragile X syndrome, thus establishing RNA editing as a novel molecular link underlying these two highly related diseases. Our findings support a role for RNA editing dysregulation in ASD pathophysiology and highlight novel mechanisms for RNA editing regulation.

2018-12-14 | GSE107895 | GEO

Widespread RNA editing dysregulation in Autism Spectrum Disorders II

2018-12-14 | GSE117776 | GEO

FMR1 targets distinct mRNA sequence elements to regulate protein expression [Affymetrix]

Project description:Fragile-X Syndrome (FXS) is a multi-organ disease leading to mental retardation, macro-orchidism in males, and premature ovarian insufficiency in female carriers. FXS is also a prominent monogenic disease associated with autism spectrum disorders (ASD). FXS is typically caused by the loss of FRAGILE X-MENTAL RETARDATION 1 (FMR1) expression, which encodes for the RNA-binding protein (RBP), FMR1 (or FMRP). We report the discovery of the RNA recognition elements (RREs), binding sites, and mRNA targets for wild-type and I304N mutant FMRP isoforms as well as its paralogs, FXR1 and FXR2. RRE frequency, ratio, and distribution determine target mRNA association with FMRP. Among highly-enriched targets, we identified many genes involved in ASD and demonstrate that FMRP can affect their protein levels in cell culture, mice, and human brain. Unexpectedly, we discovered that these targets are also dysregulated in Fmr1-/- mouse ovaries, showing signs of premature follicular overdevelopment. These results indicate that FMRP targets shared signaling pathways across different cellular contexts. As it is become increasingly appreciated that signaling pathways are important to FXS and ASD, our results here provide an invaluable molecular guide towards the pursuit of novel therapeutic targets for these devastating neurological disorders. The mRNA profile of RNA recovered from FLAG-antibody immunoprecipitated FMRP was compared to the mRNA profile of the starting lysate material.

2012-12-13 | E-GEOD-39504 | biostudies-arrayexpress

FMR1 targets distinct mRNA sequence elements to regulate protein expression [PAR-CLIP]

Project description:Fragile-X Syndrome (FXS) is a multi-organ disease leading to mental retardation, macro-orchidism in males, and premature ovarian insufficiency in female carriers. FXS is also a prominent monogenic disease associated with autism spectrum disorders (ASD). FXS is typically caused by the loss of FRAGILE X-MENTAL RETARDATION 1 (FMR1) expression, which encodes for the RNA-binding protein (RBP), FMR1 (or FMRP). We report the discovery of the RNA recognition elements (RREs), binding sites, and mRNA targets for wild-type and I304N mutant FMRP isoforms as well as its paralogs, FXR1 and FXR2. RRE frequency, ratio, and distribution determine target mRNA association with FMRP. Among highly-enriched targets, we identified many genes involved in ASD and demonstrate that FMRP can affect their protein levels in cell culture, mice, and human brain. Unexpectedly, we discovered that these targets are also dysregulated in Fmr1-/- mouse ovaries, showing signs of premature follicular overdevelopment. These results indicate that FMRP targets shared signaling pathways across different cellular contexts. As it is become increasingly appreciated that signaling pathways are important to FXS and ASD, our results here provide an invaluable molecular guide towards the pursuit of novel therapeutic targets for these devastating neurological disorders. PAR-CLIP profiling for wild-type and I304N mutant FMRP isoforms as well as paralogs, FXR1 and FXR2.

2012-12-13 | E-GEOD-39682 | biostudies-arrayexpress

(Phospho)Proteomic Characterization of Ptenm3m4 Cortex

Project description:PTEN has a strong Mendelian association with autism spectrum disorder (ASD), representing a special case in autism’s complex genetic architecture. Animal modeling for constitutional Pten mutation creates an opportunity to study how disruption of Pten affects neurobiology and glean potential insight into ASD pathogenesis. Subsequently, we comprehensively characterized the neural (phospho)proteome of Ptenm3m4/m3m4 mice, which exhibits cytoplasmic-predominant Pten expression, by applying mass spectrometry technology to their brains at two-weeks- (P14) and six-weeks-of-age (P40). The differentially expressed/phosphorylated proteins were subjected to gene enrichment, pathway, and network analyses to assess the affected biology. We identified numerous differentially expressed/phosphorylated proteins, finding greater dysregulation at P40 consistent with prior transcriptomic data. The affected pathways were largely related to PTEN function or neurological processes, while scant direct overlap was found across datasets. Network analysis pointed to ASD risk genes like Pten and Psd-95 as major regulatory hubs, suggesting they likely contribute to initiation or maintenance of cellular and perhaps organismal phenotypes related to ASD.

2022-02-17 | PXD025351 | Pride

MiR-137 and GOMAFU form a novel non-coding RNA pathway to regulate human neuron differentiation and molecular networks affected in neuropsychiatric diseases

Project description:Increasing evidence suggests important roles of long noncoding RNAs (lncRNAs) in normal neuron development and neuropsychiatric disorders that disturb early neurodevelopmental processes. One such lncRNA is GOMAFU, which displays aberrant expression in schizophrenia postmortem brains and is known to regulate SCZ-associated splice variants in developing human neurons. However, molecular mechanisms that control expression and biological function of GOMAFU in human neuron development remain elusive. Here we report the identification of a novel miRNA-lncRNA pathway in which miR-137, a well-recognized risk factor for SCZ and autism spectrum disorder (ASD) that play key roles in promoting neuronal differentiation, enhances GOMAFU expression in human neurons through targeting transcription factors that suppress GOMAFU. In addition, loss of GOMAFU in cortical neurons derived from human induced pluripotent stem cells (hiPSCs) by CRISPR-cas9 mediated gene editing significantly reduces dendritic growth during early-stage differentiation. Moreover, GOMAFU deficiency elicited a broad influence on molecular pathways commonly affected in SCZ and ASD postmortem brains, including aberrantly increased expression of numerous genes known to govern neuroimmune responses. Our studies demonstrated essential roles of the lncRNA GOMAFU in human neuron development and connected GOMAFU malfunction with pathological molecular networks in neuropsychiatric disorders.

2023-10-03 | GSE182370 | GEO

FMR1 targets distinct mRNA sequence elements to regulate protein expression [Affymetrix]

2012-12-13 | GSE39504 | GEO

FMR1 targets distinct mRNA sequence elements to regulate protein expression [PAR-CLIP]

2012-12-13 | GSE39682 | GEO

Molecular Neurobiology of Loss

Project description:Molecular Neurobiology of Loss

| PRJNA858028 | ENA

Convergent coexpression of autism associated genes suggests some novel risk genes may not be detectable in large-scale genetic studies

Project description:Autism spectrum disorder (ASD) is a highly heritable neurodevelopmental disorder characterized by deficits in social interactions and communication. Protein function altering variants in many genes have been shown to contribute to ASD risk; however, understanding the biological convergence across so many genes has been difficult and genetic studies depending on presence of deleterious variation may be limited in implicating highly intolerant genes with shorter coding sequences. Here, we demonstrate that coexpression patterns from human post-mortem brain samples (N = 993) are significantly correlated with the transcriptional consequences of CRISPR perturbations (gene editing, interference and activation) in human neurons (N = 17). Across 71 ASD risk genes, there is significant tissue-specific transcriptional convergence that implicates synaptic pathways. Tissue specific convergence of risk genes is a generalizable phenomenon, shown additionally in schizophrenia (brain) and atrial fibrillation (heart). The degree of this convergence in ASD is significantly correlated with the level of association to ASD from sequencing studies (rho = -0.32, P = 3.03 ×10−65) as well as differential expression in post-mortem ASD brains (rho = -0.23, P = 2.39×10−43). After removing all genes statistically associated with ASD, the remaining positively convergent genes showed intolerance to functional mutations, had shorter coding lengths than the ASD genes and were enriched for genes with clinical reports of potential pathogenic contribution to ASD. These results indicate that leveraging convergent coexpression can identify potentially novel risk genes that are unlikely to be discovered by sequencing studies. Overall, this work provides a simple approach to functionally proxy CRISPR perturbation, demonstrates significant context-specific transcriptional convergence among known risk genes of multiple diseases, and proposes novel ASD risk gene candidates.

2023-01-10 | GSE222259 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

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