Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

A CRISPR screen in human iPSC-derived neurons reveals convergent transcriptomic effects of neurodevelopmental disorder genes

ABSTRACT: Diverse risk genes have been identified for neurodevelopmental disorders (NDDs), but how these genes converge on similar biological pathways in neurons, and thus give rise to similar phenotypes, is unclear. Here, we apply a pooled CRISPR approach to target 23 (out of 29) NDD loss-of-function genes and examine convergent effects on gene expression across human induced pluripotent stem cell (hiPSC)-derived neural progenitor cells, glutamatergic neurons, and GABAergic neurons. Points of convergence vary between these cell-types and are greatest in mature glutamatergic neurons, where they broadly regulate synaptic, epigenetic, and, unexpectedly, mitochondrial pathways. The strongest convergent networks were observed between NDD genes with shared biological annotations, clinical associations, and co-expression patterns in human post-mortem brain. Drugs that were predicted to reverse convergent transcriptomic signatures and/or arousal and sensory processing behaviors ameliorated behavioral phenotypes in NDD model zebrafish. These results suggest that convergent effects of NDD risk genes could provide clinically useful insights. Code and secondary analysis data can be found on Synapse ( ID=syn72039767, link=https://www.synapse.org/Synapse:syn72039767/wiki/636167)

ORGANISM(S): Homo sapiens

PROVIDER: GSE319096 | GEO | 2026/03/01

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

EphrinB1 Modulates Glutamatergic Inputs into POMC Neurons and Controls Glucose Homeostasis

Project description:We aim at identifying genes enriched in POMC neurons versus NPY neurons that were involved in glutamatergic synapse formation

2020-02-07 | GSE144887 | GEO

Altered striatal actin - dynamics drives behavioral inflexibility in a mouse model of Fragile X syndrome

Project description:The proteome of glutamatergic synapses is diverse across the mammalian brain and involved in neurodevelopmental disorders (NDDs). Among those is Fragile X syndrome (FXS), an NDD caused by the dysfunctional RNA binding protein FMRP. Here we demonstrate how the brain region-specific composition of post-synaptic density (PSD) contributes to FXS. The FXS mouse model shows, in the striatum, an altered association of the PSD with the actin cytoskeleton, reflecting immature dendritic spine morphology and reduced synaptic actin dynamics. Enhancing actin turnover with constitutively active RAC1 ameliorates these deficits. At the behavioral level, the FXS model displays striatal-driven inflexibility, a typical feature of FXS individuals, that is rescued by exogenous RAC1. Striatal ablation of Fmr1 is sufficient to recapitulate behavioral impairments observed in the FXS model. These results indicate that dysregulation of synaptic actin dynamics in the striatum, a region largely unexplored in FXS, contributes to the manifestation of FXS behavioral phenotypes.

2023-06-08 | PXD040331 | Pride

Sleep need driven oscillation of glutamatergic synaptic phenotype

Project description:The response to sleep loss, induced by experimental sleep deprivation (SD), provides insight into the function of sleep. Earlier observations have shown an overall increase in synaptic strength and number of cortical, glutamate, AMPA receptor (AMPAR) synapses in response to SD that is recovered by sleep. However, other aspects of glutamatergic transmission, including NMDA receptor mediated neurotransmission and related upstream synaptic regulators of the glutamate synapse function, have not been well examined. Following SD, we report increased AMPA/NMDA ratio in whole cell recordings of frontal cortical (FC) pyramidal neurons of layers 2-3. Additionally, the ratio of silent/active synapse is decreased after SD reflecting decreased silent synapses and plastic potential to convert silent NMDA to active AMPA synapses. All aspects recover with sleep and are associated with differentially expressed genes (DEGs) affecting glutamatergic synaptic phenotype. The DEGs are enriched for a functional group of synaptic shaping cellular components (SSCs) controling glutamate synapse phenotype, overlap with autism risk genes and are primarily observed in a subtype of excitatory pyramidal neurons that project intra-telencephalically (ExIT neurons). Upstream, sleep-related control is suggested by significant enrichment of genes controlled by transcription factor, MEF2c and nuclear HDAC4, a repressor of MEF2c transcriptional activation. Taken together, we propose a functional role of sleep/wake in FC controlling gene expression, regulating an oscillation of glutamate-synaptic phenotypes that facilitates motor learning and training, and if dysfunctional, increases risk for autism.

2025-02-10 | GSE256140 | GEO

SETD5 haploinsufficiency affects mitochondrial compartment in neural cells

Project description:Neurodevelopmental disorders (NDDs) are heterogeneous conditions due to alterations of a variety of molecular mechanisms and cell dysfunctions. Epigenetic basis of NDDs have been reported in an increasingly number of cases while mitochondrial dysfunctions are more common within NDD patients than in the general population. Here, we investigated experimental models of Setd5 haploinsufficiency, that leads to NDDs in humans due to chromatin defects, and uncovered that mitochondrial dysfunction participates in the pathogenesis. Mitochondrial impairment is facilitated by transcriptional aberrations that follow the decrease of SETD5 enzyme. Low levels of SETD5 resulted in fragmented mitochondria, less mitochondrial potential and ATP production both in neural precursors and neurons. Mitochondria were miss-localized in mutant neurons, with few organelles within neurites and synapses. Our study explores the epigenetics/mitochondria interplay as an important aspect of NDD pathophysiology and defines the impairments of mitochondrial functionality and dynamics as new therapeutic targets for disorders associated with loss of SETD5.

2023-01-05 | GSE222188 | GEO

Proteome analysis of cumulative antenatal and postnatal environmental exposure in the brain of mice

Project description:Environmental exposures across critical developmental windows can significantly influence brain development and contribute to the risk of neurodevelopmental disorders (NDDs). Importantly, emerging clinical evidence suggests that multiple environmental factors during early development result in more pronounced disease phenotypes in offspring. To expand upon this existing notion, we developed a ‘triple-hit’ mouse model to examine the combined effects of maternal social stress, chronic high-fat diet consumption, and early life poly(I:C) exposure on long-term developmental outcomes in offspring. We observed that ‘triple-hit’ male offspring displayed autism-like social deficits and an overall increased susceptibility to NDD-like behavioural alterations in adulthood. Single-cell RNA (scRNA) transcriptomic and bulk proteomic analyses were performed in male triple hit offspring in brain tissue. The results are discussed in the associated publication.

2026-01-19 | PXD060752 | Pride

The ChAHP chromatin remodelling complex regulates neurodevelopmental disorder risk genes to scale the production of neocortical layers

Project description:Although chromatin remodellers are among the most important risk genes associated with neurodevelopmental disorders (NDDs), the roles of these complexes during brain development are in many cases unclear. Here, we focused on the recently discovered ChAHP chromatin remodelling complex. The zinc finger and homeodomain transcription factor ADNP is a core subunit of this complex, andde novo ADNPmutations lead to intellectual disability and autism spectrum disorder. However, germlineAdnpknockout mice were previously shown to exhibit early embryonic lethality, obscuring subsequent roles for the ChAHP complex in neurogenesis. Here, we employed single cell transcriptomics, cut&run-seq, and histological approaches to characterize mice conditionally ablated for the ChAHP subunitsAdnpandChd4. We show that during neocortical development, Adnp and Chd4 orchestrate the production of late-born, upper-layer neurons through a two-step process. First, Adnp is required to sustain progenitor proliferation specifically during the developmental window for upper-layer cortical neurogenesis. Accordingly, we found that Adnp recruits Chd4 to genes associated with progenitor proliferation. Second, in postmitotic differentiated neurons, we define a network of risk genes linked to NDDs that are regulated by Adnp and Chd4. Taken together, these data demonstrate that ChAHP is critical for driving the expansion upper-layer cortical neurons, and for regulating neuronal gene expression programs, suggesting that these processes may potentially contribute to NDD etiology.

2024-12-30 | GSE262584 | GEO

The ChAHP chromatin remodelling complex regulates a network of neurodevelopmental disorder risk genes to scale the production of neocortical layers (cut&run-seq)

Project description:Although chromatin remodellers are among the most important risk genes associated with neurodevelopmental disorders (NDDs), the roles of these complexes during brain development are in many cases unclear. Here, we focused on the recently discovered ChAHP chromatin remodelling complex. The zinc finger and homeodomain transcription factor ADNP is a core subunit of this complex, and de novo ADNP mutations lead to intellectual disability and autism spectrum disorder. However, germline Adnp knockout mice were previously shown to exhibit early embryonic lethality, obscuring subsequent roles for the ChAHP complex in neurogenesis. Here, we employed single cell transcriptomics, cut&run-seq, and histological approaches to characterize mice conditionally ablated for the ChAHP subunits Adnp and Chd4. We show that during neocortical development, Adnp and Chd4 orchestrate the production of late-born, upper-layer neurons through a two-step process. First, Adnp is required to sustain progenitor proliferation specifically during the developmental window for upper-layer cortical neurogenesis. Accordingly, we found that Adnp recruits Chd4 to genes associated with progenitor proliferation. Second, in postmitotic differentiated neurons, we define a network of risk genes linked to NDDs that are regulated by Adnp and Chd4. Taken together, these data demonstrate that ChAHP is critical for driving the expansion upper-layer cortical neurons, and for regulating neuronal gene expression programs, suggesting that these processes may potentially contribute to NDD etiology.

2024-12-29 | GSE255599 | GEO

Knockout screens reveal genes and pathways essential for neuronal differentiation and implicate PEDS1 in neurodevelopment

Project description:Neurodevelopmental disorders (NDDs) arise from disruptions in brain development, yet the underlying pathways remain incompletely understood. Here, we demonstrate that genome-wide CRISPR knockout screens in mouse embryonic stem cells differentiating into neural lineages identify hundreds of essential genes, only a minority of which are currently implicated in NDDs. Dominant NDD genes were enriched for transcriptional regulators, whereas recessive NDD genes were predominantly involved in metabolic processes. Mouse models for eight genes (Eml1, Dusp26, Dynlrb2, Mta3, Peds1, Sgms1, Slitrk4 and Vamp3) revealed marked neuroanatomical abnormalities, including microcephaly in half of the cases. Focusing on PEDS1, a key enzyme in plasmalogen biosynthesis, we identified a bi-allelic variant in individuals with microcephaly, global developmental delay and congenital cataracts. In mice, Peds1 deficiency led to accelerated cell-cycle exit and impaired neuronal differentiation and migration. These pathways required for neural differentiation provide a genetic framework for discovering additional NDD genes.

2025-10-19 | GSE295884 | GEO

Effect of influenza A virus infection during pregnancy on the developing fetal brain

Project description:Epidemiological studies link NDDs with exposure to maternal viral infection in utero. As the immature brain is vulnerable to insult, it is thought that prenatal inflammation alters neurodevelopmental trajectories, leading to NDD pathologies. Using a biologically relevant mouse model of live influenza (flu) infection during pregnancy, we aim to determine if gestational flu infection triggers detrimental maternal cell signaling that leads to NDD-relevant pathologies in offspring. Overall, this work will improve translation to the clinic and will build a foundation for developing targeted therapeutics for NDDs that can be delivered during gestation.

2024-06-20 | GSE262291 | GEO

ZMYND11 Functions in Bimodal Regulation of Latent Genes and Brain-like Splicing to Safeguard Corticogenesis [CUT&RUN]

Project description:While the identification of pathogenic variants linked to neurodevelopmental (NDD) and autism spectrum disorders (ASD) has advanced rapidly, the mechanisms underlying these genetic risks remain unclear. Here, we leveraged a human pluripotent stem cell model to uncover the neurodevelopmental consequences of mutations in ZMYND11, a newly implicated risk gene. ZMYND11, known for its tumor suppressor function, encodes a histone-reader that recognizes sites of transcriptional elongation and acts as a co-repressor. Our findings reveal that ZMYND11 deficient cortical neural stem cells exhibit upregulation expression of latent developmental pathways, leading to impaired production of secondary neural progenitors and neurons. In addition to its chromatin-related functions, we found ZMYND11 orchestrates a brain specific isoform switch that affects migration and proliferation of cortical neural stem cells. We further demonstrated that brain specificity is likely to involve the activity of the splicing regulator RBFOX2. Finally, we extended our findings to 10 additional lines with different chromatin-related NDD/ASD risk factors and identified a subset displaying similar activation of developmental pathways and splicing dysregulation, which could partially be rescued by leveraging the transcriptional repression and splicing coordination of ZMYND11. Collectively, our work highlights the critical role of ZMYND11 in regulating developmental signals and alternative splicing, offering novel insights into the molecular pathology of ZMYND11-associated NDDs. Moreover, these findings suggest broader convergence with other genetic risk factors for NDD/ASD, presenting potential therapeutic avenues for intervention.

2025-08-21 | GSE279068 | 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