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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE237297 | GEO | 2025/04/17

REPOSITORIES: GEO

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

Project description: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.

2025-04-17 | GSE237165 | 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

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

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

| PRJNA994099 | 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

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

Recapitulation and reversal of schizophrenia-related phenotypes in Setd1a-deficient mice

Project description:SETD1A, a histone methyltransferase, is a key schizophrenia susceptibility gene. Mutant mice carrying a heterozygous loss-of-function mutation of the orthologous gene exhibit alterations in axonal branching and cortical synaptic dynamics, accompanied by specific deficits in working memory that recapitulates SCZ-related alterations. We show that Setd1a targets mostly enhancers and reveal a striking overlap between Setd1a and Mef2 chromatin targets. Setd1a targets are highly expressed in pyramidal neurons and enriched for genes with postnatally-biased expression involved in synaptic structure and function. Notably, evolutionary conserved Setd1a binding sites and target genes are strongly associated with neuropsychiatric genetic risk burden. Reinstating Setd1a expression in adulthood rescues working memory deficits. We identify LSD1 as a major demethylase counteracting the effects of Setd1a methyl transferase activity and show that LSD1 antagonism in adult Setd1a-deficient mice results in a full rescue of the behavioral abnormalities and axonal branching deficits. Our findings advance our understanding of how SETD1A mutations predispose to SCZ and point to therapeutic interventions.

2019-10-09 | GSE123652 | GEO

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