Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Genomic and transcriptomic profiles underlying the effect of SETD1A disruption on human neurodevelopmental trajectories

ABSTRACT: To examine the transcriptomic alteration by SETD1A deficiency, combining CRISPR/CAS9 genome editing and 3-Dimentional Cell Culture technology, we generated organoid models of the developing human cerebral cortex derived from isogenic human induced pluripotent stem cells (hiPSCs) modified to carry a SETD1A LoF schizophrenia risk mutation. We then performed gene expression profiling analysis using data obtained from RNA-seq of WT and mutant cortical neurons at DIV70.

ORGANISM(S): Homo sapiens

PROVIDER: GSE237165 | GEO | 2025/04/17

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Genomic and transcriptomic profiles underlying the effect of SETD1A disruption on human neurodevelopmental trajectories [ChIP-seq]

Project description:To examine the genomic alteration by SETD1A deficiency, combining CRISPR/CAS9 genome editing and 3-Dimentional Cell Culture technology, we generated organoid models of the developing human cerebral cortex derived from isogenic human induced pluripotent stem cells (hiPSCs) modified to carry a SETD1A LoF schizophrenia risk mutation. We then performed genomic profiling analysis using data obtained from CUT&Tag of WT and mutant cortical neurons at DIV70.

2025-04-17 | GSE237297 | GEO

Developmental disruption to the cortical transcriptome and synaptosome in a model of SETD1A loss-of-function

Project description:Large-scale genomic studies of schizophrenia implicate genes involved in the epigenetic regulation of transcription by histone methylation and genes encoding components of the synapse. However, the interactions between these pathways in conferring risk to psychiatric illness are unknown. Loss-of-function (LoF) mutations in the gene encoding histone methyltransferase, SETD1A, confer substantial risk to schizophrenia. Among several roles, SETD1A is thought to be involved in the development and function of neuronal circuits. Here, we employed a multi-omics approach to study the effects of heterozygous Setd1a LoF on gene expression and synaptic composition in mouse cortex across five developmental timepoints from embryonic day 14 to postnatal day 70. Using RNA sequencing, we observed that Setd1a LoF resulted in the consistent downregulation of genes enriched for mitochondrial pathways. This effect extended to the synaptosome, in which we found age-specific disruption to both mitochondrial and synaptic proteins. Using large-scale patient genomics data, we observed no enrichment for genetic association with schizophrenia within differentially expressed transcripts or proteins, suggesting they derive from a distinct mechanism of risk from that implicated by genomic studies. This study highlights biological pathways through which SETD1A loss-of-function may confer risk to schizophrenia. Further work is required to determine whether the effects observed in this model reflect human pathology.

2022-05-26 | PXD032742 | Pride

Developmental disruption to the cortical transcriptome and synaptosome in a model of SETD1A loss-of-function

Project description:We employed a multi-omics approach to study the effects of heterozygous Setd1a LoF on gene expression and synaptic composition in mouse cortex across five developmental timepoints from embryonic day 14 to postnatal day 70. Using RNA sequencing, we observed that Setd1a LoF resulted in the consistent downregulation of genes enriched for mitochondrial pathways. This effect extended to the synaptosome, in which we found age-specific disruption to both mitochondrial and synaptic proteins.

2022-05-02 | GSE199428 | GEO

Scaled and efficient derivation of loss-of-function alleles in risk genes for neurodevelopmental and psychiatric disorders in human iPSCs

Project description:Translating genetic findings for neurodevelopmental and psychiatric disorders (NPD) into actionable disease biology would benefit from large-scale and unbiased functional studies of NPD genes. Leveraging the cytosine base editing (CBE) system, here we developed a pipeline for clonal loss-of-function (LoF) allele mutagenesis in human induced pluripotent stem cells (hiPSCs) by introducing premature stop-codons (iSTOP) that lead to mRNA nonsense-mediated-decay (NMD) or protein truncation. We tested the pipeline for 23 NPD genes on 3 hiPSC lines and achieved highly reproducible, efficient iSTOP editing in 22 NPD genes. Using RNAseq, we confirmed their pluripotency, absence of chromosomal abnormalities, and NMD. Interestingly, for three schizophrenia risk genes (SETD1A, TRIO, CUL1), despite the high efficiency of base editing, we only obtained heterozygous LoF alleles, suggesting their essential roles for cell growth. We replicated the reported neural phenotypes of SHANK3-haploinsufficiency and found CUL1-LoF reduced neurite branches and synaptic puncta density. This iSTOP pipeline enables a scaled and efficient LoF mutagenesis of NPD genes, yielding an invaluable shareable resource.

2024-09-17 | GSE262442 | GEO

Genomic and transcriptomic profiles underlying the effect of SETD1A disruption on human neurodevelopmental trajectories

Project description:Genomic and transcriptomic profiles underlying the effect of SETD1A disruption on human neurodevelopmental trajectories

| PRJNA994099 | ENA

DNA methylation in frontal cortex of Setd1a haploinsufficient mice

Project description:SETD1A, a histone methyltransferase, is implicated in schizophrenia through rare loss-of-function mutations. While SETD1A regulates gene expression via histone H3K4 methylation, its influence on broader epigenetic dysregulation remains incompletely understood. We explored the hypothesis that SETD1A haploinsufficiency contributes to neurodevelopmental disruptions associated with schizophrenia risk via alterations in DNA methylation. We profiled DNA methylation in the frontal cortex of Setd1a+/- mice across prenatal and postnatal development using Illumina Mouse Methylation arrays. Differentially methylated positions and regions were identified, and their functional relevance examined through gene and biological annotation. We integrated these findings with transcriptomic and proteomics datasets, and assessed mitochondrial complex I activity to explore potential downstream functional effects. Setd1a haploinsufficiency resulted in widespread hypomethylation of genes related to ribosomal function and RNA processing that persisted across all developmental stages. Setd1a-targeted promoter regions and noncoding small nucleolar RNAs (snoRNAs) were also enriched for differentially methylated sites. Despite the downregulation of mitochondrial gene expression, the same genes were not differentially methylated and complex I activity in Setd1a+/- mice did not differ significantly from controls. Genes overlapping hypomethylated regions were enriched for common genetic associations with schizophrenia. Our findings suggest that SETD1A haploinsufficiency disrupts the epigenetic regulation of ribosomal pathways. These results provide insight into an alternative mechanism through which genetic variation in SETD1A influences developmental and synaptic plasticity, contributing to schizophrenia pathophysiology.

2025-04-22 | GSE295008 | GEO

Genomic and transcriptomic profiles underlying the effect of SETD1A disruption on human neurodevelopmental trajectories (scRNA-Seq)

Project description:To dissect, in more detail, cell population alterations and examine in situ genotypic differences in transcriptomic and regulatory profiles during neurogenesis and neuronal differentiation, we used single cell RNA sequencing (scRNA-seq) to profile cell type composition and molecular signatures of FOs derived from mutant and control iPSC lines at DIV70

2025-04-17 | GSE239864 | GEO

Genomic and transcriptomic profiles underlying the effect of SETD1A disruption on human neurodevelopmental trajectories [ChIP-seq]

Project description:Genomic and transcriptomic profiles underlying the effect of SETD1A disruption on human neurodevelopmental trajectories [ChIP-seq]

| PRJNA994538 | ENA

Genomic and transcriptomic profiles underlying the effect of SETD1A disruption on human neurodevelopmental trajectories (scRNA-Seq)

Project description:Genomic and transcriptomic profiles underlying the effect of SETD1A disruption on human neurodevelopmental trajectories (scRNA-Seq)

| PRJNA1001298 | ENA

Transcriptional changes following cellular knockdown of the schizophrenia risk gene SETD1A are enriched for common variant association with the disorder

Project description:Loss of function mutations in SETD1A are the first experiment-wide significant findings to emerge from exome sequencing studies of schizophrenia. Although SETD1A is known to encode a histone methyltransferase, the consequences of reduced SETD1A activity on gene expression in neural cells have, to date, been unknown. To explore transcriptional changes through which genetic perturbation of SETD1A could confer risk for schizophrenia, we have performed genome-wide gene expression profiling of a commonly used human neuroblastoma cell line in which SETD1A expression has been experimentally reduced using RNA interference (RNAi). We identified 1031 gene expression changes that were significant in two separate RNAi conditions compared with control, including effects on genes of known neurodevelopmental importance such as DCX and DLX5. Genes that were differentially expressed following SETD1A knockdown were enriched for annotation to metabolic pathways, peptidase regulator activity and integrin-mediated regulation of cell adhesion. Moreover, differentially expressed were enriched for common variant association with schizophrenia, suggesting a degree of molecular convergence between this rare schizophrenia risk factor and susceptibility variants for the disorder operating more generally.

2019-01-05 | GSE118941 | 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