Network effects of the 15q13.3 microdeletion on the transcriptome and epigenome in human induced neurons
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ABSTRACT:
PROVIDER: PRJNA557485 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR11464600_1.fastq.gz | Fastqsanger.gz | |||
| SRR11464600_2.fastq.gz | Fastqsanger.gz | |||
| SRR11464601_1.fastq.gz | Fastqsanger.gz | |||
| SRR11464601_2.fastq.gz | Fastqsanger.gz | |||
| SRR11464555_1.fastq.gz | Fastqsanger.gz |
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Project description:Background: Deletions in the 15q13.3 region are associated with several neuropsychiatric disorders, including autism and schizophrenia. Association studies in humans and functional studies in mice have suggested that several genes within the 15q13.3 microdeletion may play a role in neuronal dysfunction, but the intermediate molecular mechanisms remain unknown. Methods: Induced pluripotent stem cells from 3 patients with the 15q13.3 microdeletion and 3 sex-matched controls were generated and converted into induced neurons. We analyzed the genome-wide effects of the 15q13.3 microdeletion on gene expression, DNA methylation, chromatin accessibility, and sensitivity to cisplatin-induced DNA damage. We also evaluated gene expression changes in induced neurons containing CRISPR knockouts of single 15q13.3 microdeletion genes. Results: In both cell types, gene copy number change within the 15q13.3 microdeletion was accompanied by significantly decreased gene expression and no compensatory changes in DNA methylation or chromatin accessibility, supporting the model that haploinsufficiency of genes within the deleted region drives the disorder. Further, we observed global effects of the microdeletion on the transcriptome and epigenome, with disruptions in several neuropsychiatric disorder-associated pathways, such as Wnt signaling, ribosome biogenesis, DNA binding, and cell adhesion. Conclusions: Our multi-omics analyses of the 15q13.3 microdeletion revealed downstream effects in pathways previously associated with neuropsychiatric disorders. This molecular systems analysis can also be applied to other brain relevant chromosomal aberrations to further our etiological understanding of neuropsychiatric disorders.
2021-03-28 | GSE135131 | GEO
Project description:BackgroundThe 15q13.3 microdeletion is associated with several neuropsychiatric disorders, including autism and schizophrenia. Previous association and functional studies have investigated the potential role of several genes within the deletion in neuronal dysfunction, but the molecular effects of the deletion as a whole remain largely unknown.MethodsInduced pluripotent stem cells, from 3 patients with the 15q13.3 microdeletion and 3 control subjects, were generated and converted into induced neurons. We analyzed the effects of the 15q13.3 microdeletion on genome-wide gene expression, DNA methylation, chromatin accessibility, and sensitivity to cisplatin-induced DNA damage. Furthermore, we measured gene expression changes in induced neurons with CRISPR (clustered regularly interspaced short palindromic repeats) knockouts of individual 15q13.3 microdeletion genes.ResultsIn both induced pluripotent stem cells and induced neurons, gene copy number change within the 15q13.3 microdeletion was accompanied by significantly decreased gene expression and no compensatory changes in DNA methylation or chromatin accessibility, supporting the model that haploinsufficiency of genes within the deleted region drives the disorder. Furthermore, we observed global effects of the microdeletion on the transcriptome and epigenome, with disruptions in several neuropsychiatric disorder-associated pathways and gene families, including Wnt signaling, ribosome function, DNA binding, and clustered protocadherins. Individual gene knockouts mirrored many of the observed changes in an overlapping fashion between knockouts.ConclusionsOur multiomics analysis of the 15q13.3 microdeletion revealed downstream effects in pathways previously associated with neuropsychiatric disorders and indications of interactions between genes within the deletion. This molecular systems analysis can be applied to other chromosomal aberrations to further our etiological understanding of neuropsychiatric disorders.
| S-EPMC9359316 | biostudies-literature
Project description:The edited lines introduced a premature termination at rs757148409/p.Arg89Ter. The mutant iNs showed a ~50% decrease in OTUD7A protein expression without undergoing nonsense-mediated mRNA decay. The mutant iNs also exhibited marked reduction of dendritic complexity, synaptic puncta density of AMPA receptor subunit GluA1 and postsynaptic scaffold PSD-95, as well as neural firing rate and network activity. Congruent with the neural phenotypic alterations in mutant iNs, our transcriptomic analysis showed that the set of OTUD7A LoF downregulated genes was significantly enriched for synapse development and function, and was associated with SZ and other neuropsychiatric disorders. These results suggest that the OTUD7A LoF mutation rs757148409 impairs neurodevelopment and synaptic function in human neurons, providing mechanistic insight into the possible role of OTUD7A in driving neuropsychiatric phenotypes associated with the 15q13.3 microdeletion.
2021-11-28 | GSE189614 | GEO
Project description:Dysfunction of the thalamocortical pathway has been implicated in multiple psychiatric disorders, but mechanisms by which these defects emerge remain poorly understood. We explored this question in the context of the 22q11.2 microdeletion, which represents a significant genetic risk for schizophrenia, leveraging emerging technologies of in vitro brain organogenesis using chimeric brain organoids derived from human induced pluripotent stem cells. Here we show that the 22q11.2 microdeletion leads to transcriptional dysregulation in thalamic organoids that is enriched for psychiatric disease risk genes, including elevated expression of FOXP2, which represents the most significantly dysregulated transcription factor in glutamatergic neurons and astroctyes. In a co-culture model fusing thalamic and cortical organoids, we demonstrate that the 22q11.2 deletion mediates an overgrowth of thalamic axons via overexpression of FOXP2, which then subsequently mediates the overgrowth of reciprocal corticothalamic axons. Dysregulation of FOXP2 leads to downregulation of ROBO2, an axon repulsive receptor important for thalamocortical axon pathfinding, and knockdown of ROBO2 in control organoids phenocopies excessive outgrowth of thalamic axons. Together, our study suggests that early steps in thalamocortical pathway development may be dysregulated in a model of genetic risk for schizophrenia, and contribute to neural phenotypes in 22q11.2 microdeletion syndrome.
2024-02-22 | GSE245719 | GEO
Project description:Modeling OTUD7A loss-of-function mutation in schizophrenia-associated 15q13.3 microdeletion in human neurons
| PRJNA783895 | ENA
Project description:Single cell transcriptome analysis of the effect of the 16p11.2 microdeletion on hIPSC derived developing human GABAergic neurons
| PRJEB46758 | ENA
Project description:We identified a family with a novel chromosome 13 microdeletion associated with a syndromic form of corneal opacification. In order to determine which genes in/around the microdeletion were contributing to the constellation of phenotypes, a corneal epithelial sample was obtained during a superficial keratectomy of the proband's 9-year-old brother.
2023-08-11 | GSE230430 | GEO
Project description:Background: The 15q13.3 microdeletion has pleiotropic effects ranging from apparently healthy to severely affected individuals with intellectual disability, epilepsy, and neuropsychiatric disorders. Previous studies have investigated several genes within the deletion as potential drivers, but the pathomechanism and the underlying basis of the variable phenotype remain elusive. Methods: We analyzed the effects of the 15q13.3 microdeletion on genome-wide gene expression using native RNA-seq data from blood of 3 probands with the 15q13.3 microdeletion and 4 sex- and age-matched control subjects. We assessed differentially expressed genes (DEGs), gene ontology (GO) enrichment, protein-protein interaction (PPI) functional modules, as well as gene expression in different brain developmental stages. Results: The haploinsufficiency of genes within the deleted region was not transcriptionally compensated, suggesting that a dosage effect may contribute to the pathomechanism. Although GO and PPI showed that regulation of gene expression is perturbed, we could not identify a singular driving transcription factor. We observed network-wide dysregulatory effects suggesting that the phenotype is not caused by a singular critical gene. A significant proportion of DEGs, which are silenced in the adult brain, have maximum expression during the prenatal stage of brain development. Based on DEGs and their PPI partners we identified altered functional modules related to immune and inflammatory processes, as well as nervous system development. Conclusions: We show that the 15q13.3 microdeletion has a ubiquitous impact on transcriptome pattern, especially dysregulation of genes involved in brain development. The effect on immune and inflammatory responses cannot be fully assessed based on the test material, i.e. blood. Possibly, the high phenotypic variability seen in 15q13.3 microdeletion could stem from an increased vulnerability during brain development, instead of a specific pathomechanism.
2022-08-08 | GSE197903 | GEO
Project description:Epigenome-wide association study in peripheral white blood cells: Methyl Epigenome Network Association (MENA) project
| PRJNA474471 | ENA