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Network Effects of the 15q13.3 Microdeletion on the Transcriptome and Epigenome in Human-Induced Neurons

      Abstract

      Background

      The 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.

      Methods

      Induced 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.

      Results

      In 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.

      Conclusions

      Our 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.

      Keywords

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      Linked Article

      • Cross-Platform Validation of 15q13.3 Microdeletion Network Effects in Human Neurons
        Biological PsychiatryVol. 89Issue 5
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          Heterozygous copy number variants are highly penetrant and pleiotropic deletions or duplications that confer risk to a variety of neuropsychiatric disease (1). Among these, 15q13.3 microdeletions (∼1.5–2.0 Mbp) result in developmental/intellectual disability, schizophrenia, autism spectrum disorder, and epilepsy, among other conditions, affecting a core set of 7 protein-coding genes (CHRNA7, FAN1, TRPM1, KLF13, OTUD7A, MTMR10, and ARHGAP11B), and 1 microRNA (MIR211) (2). While previous studies nominated candidate genes to explain the psychiatric symptoms associated with the microdeletion, the network effects of the gene cluster have yet to be explored under a human neuronal model.
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      • Errata
        Biological PsychiatryVol. 89Issue 5
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          Erratum to: “Network Effects of the 15q13.3 Microdeletion on the Transcriptome and Epigenome in Human-Induced Neurons,” by Zhang et al. (Biol Psychiatry 2021; 89:497–509); https://doi.org/10.1016/j.biopsych.2020.06.021 .
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