GSE135131
Network effects of the 15q13.3 microdeletion on the transcriptome and epigenome in human induced neurons
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. Overall design: 15q13.3 microdeletion and control iPSCs and iNs were analyzed with RNA-seq, Methyl-seq, and ATAC-seq. CRISPR knockout iNs were analyzed with RNA-seq.