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Network effects of the 15q13.3 microdeletion on the transcriptome and epigenome in human induced neurons

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE135131 | GEO | 2021/03/28

REPOSITORIES: GEO

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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.

Project description:Copy number variants at chromosome 15q13.3 contribute to liability for multiple intellectual and developmental disabilities (IDDs) including Autism Spectrum Disorder (ASD). Individuals with duplications of this interval, which includes the gene CHRNA7, have IDDs with variable penetrance. However, the basis of such differential affectation remains uncharacterized.Methods: Induced pluripotent stem cell (iPSC) models were generated from two first degree relatives with the same 15q13.3 duplication, a boy with distinct features of autism and emotional dysregulation (the affected proband, AP) and his clinically unaffected mother (the UM). These models were compared to unrelated control subjects lacking this duplication (UC, male and female). iPSC-derived neural progenitors and cortical neuroids consisting of cortical excitatory and inhibitory neurons were used to model potential contributors to neuropsychiatric impairment. Results: The AP-derived model uniquely exhibited disruptions of cellular physiology and neurodevelopment not observed in either the UM or in unrelated male and female controls. These included enhanced neural progenitor proliferation but impaired neuronal differentiation, maturation, and migration, and increased endoplasmic reticulum (ER) stress in neural progenitors. Both the AP’s neuronal migration deficit and elevated ER stress could be selectively rescued by different pharmacologic agents. Neuronal gene expression was also specifically dysregulated in the AP, including altered expression of genes related to behavior, psychological disorders, neuritogenesis, neuronal migration, and WNT signaling. By contrast with these AP-specific phenotypes, both the AP- and UM-derived neurons exhibited shared alterations of neuronal function, including elevated cholinergic activity consistent with increased homomeric CHRNA7 channel activity.Conclusion: Together, these data define both affectation-specific phenotypes seen only in the AP, as well as abnormalities observed in both individuals with CHRNA7 duplication, the AP and UM, but not in UC-derived neurons. This is, to our knowledge, the first study to use a human stem cell-based platform to study the basis of variable affectation in cases of 15q13.3 duplication at the cellular, molecular, and functional levels. This work suggests potential approaches for suppressing abnormal neurodevelopment or physiology that may contribute to severity of affectation in this proband. Some of these AP-specific neurodevelopmental anomalies, or the functional anomalies observed in both 15q13.3 duplication carriers (the AP and UM), could also contribute to the differential phenotypic penetrance seen in other individuals with 15q13.3 duplication.

Project description:Abstract: Noncoding variants of presumed regulatory function contribute to neuropsychiatric disease heritability. 4442 noncoding variants connected to risk for 10 neuropsychiatric disorders, including autism spectrum disorder, attention deficit hyperactivity disorder, bipolar disorder, borderline personality disorder, major depression, generalized anxiety disorder, panic disorder, post-traumatic stress disorder, obsessive-compulsive disorder, and schizophrenia, were studied within developing human neural cells. Integrating epigenomic and transcriptomic data with massively parallel reporter assays identified 637 disease-associated single-nucleotide variants (daSNVs) with altered transcription-regulating activity. Expression-gene mapping, network analyses, and chromatin looping identified 619 candidate disease-relevant target genes modulated by these daSNVs. Specific daSNV-associated molecular pathways mapped to prevalent mental health symptoms. These data provide a framework resource to study inherited pathogenic risk for human neuropsychiatric disorders. Purpose: To place disease-associated single nucleotide variants (daSNVs) in genomic context within human neural cells, matched RNA-seq, chromatin accessibility profiling via ATAC-seq, and enhancer-promoter looping via H3K27ac HiChIP was performed in ES cells and at day 2 (N-D2), 10 (N-D10), and 28 (N-D28) of neuronal differentiation. Additionally, anterior (A-NPC) and posterior (P-NPC) neuronal stem cells were generated and studied. Matched sequencing was also performed on primary human astrocytes from adult brains. Processed data for all cell types can be found in this repository. Raw data D10 and D28 RNA seq samples can be found here. Raw data for D0, D2, A-NSC, A-D2, P-NSC, and P-D2 data can be found here: https://www.biorxiv.org/content/10.1101/2020.12.02.398677v1.abstract. Raw data for Astrocytes can be found with the Donohue, et al. "The combinatorial cis-regulatory vocabulary of cell type-specific gene regulation in homeostasis and disease".

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Network effects of the 15q13.3 microdeletion on the transcriptome and epigenome in human induced neurons

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