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Activity-Dependent Transcriptional Program in NGN2+ Neurons Enriched for Genetic Risk for Brain-Related Disorders

ABSTRACT: We generated human-induced pluripotent stem cell (hiPSC) derived neurons isolated from six childhood-onset schizophrenia (COS) cases and five healthy controls. To measured the transcriptional and epigenomic changes following neuronal activation with KCl, we harvested these cells one and six hours after stimulation with 50mM KCl and under non-stimulating conditions, followed by RNA-seq and ATAC-seq profiling. We comprehensively characterized activity-dependent changes in gene expression and gene regulatory element activity (chromatin accessibility) in hiPSC-derived neurons. After one hour of KCl induced depolarization, neurons invoked substantial activity-dependent changes in the expression of genes regulating synaptic functions, some of which are known to be perturbed in neuropsychiatric diseases, including schizophrenia and autism spectrum disorder. By capturing changes in chromatin accessibility, we extended our analysis to activity-dependent gene regulatory elements, captured by changes in chromatin accessibility, and also found significant heritability enrichment for schizophrenia variants in the activity-induced enhancers. Our framework not only offers an alternative approach to study the mechanisms of COS but also adds to converging evidence that activity-induced expression changes mediated by the activity of regulatory elements might contribute to schizophrenia risk.

ORGANISM(S): Homo sapiens

PROVIDER: GSE203082 | GEO | 2023/07/14

REPOSITORIES: GEO

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Project description:Cell-based models of many neurological and psychiatric diseases, established by reprogramming patient somatic cells into human induced pluripotent stem cells (hiPSCs), have now been reported. While numerous reports have demonstrated that neuronal cells differentiated from hiPSCs are electrophysiologically active mature neurons, the âageâ of these cells relative to cells in the human brain remains unresolved. Comparisons of gene expression profiles of hiPSC-derived neural progenitor cells (NPCs) and neurons to the Allen BrainSpan Atlas indicate that hiPSC neural cells most resemble first trimester neural tissue. Consequently, we posit that hiPSC-derived neural cells may most accurately be used to model the early developmental defects that contribute to disease predisposition rather than the late features of the disease. Though the characteristic symptoms of schizophrenia SZ generally appear late in adolescence, it is now thought to be a neurodevelopmental condition, often predated by a prodromal period that can appear in early childhood. Postmortem studies of SZ brain tissue typically describe defects in mature neurons, such as reduced neuronal size and spine density in the prefrontal cortex and hippocampus, but abnormalities of neuronal organization, particularly in the cortex, have also been reported. We postulated that defects in cortical organization in SZ might result from abnormal migration of neural cells. To test this hypothesis, we directly reprogrammed fibroblasts from SZ patients into hiPSCs and subsequently differentiated these disorder-specific hiPSCs into NPCs. SZ hiPSC differentiated into forebrain NPCs have altered expression of a number of cellular adhesion genes and WNT signaling. Methods: We compared global transcription of forebrain NPCs from six control and four SZ patients by RNAseq. Results: Multi-dimensional scaling (MDS) resolved most SZ and control hiPSC NPC samples; 848 genes were significantly differentially expressed (FDR<0.01) Conclusions: The WNT signaling pathway was enriched 2-fold (fisher exact test p-value = 0.031). 1-2 independent differentiations (biological replicates) for each of four control and four schizophrenia patients were analyzed; samples were generated in parallel to neuron RNAseq data.

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Activity-Dependent Transcriptional Program in NGN2+ Neurons Enriched for Genetic Risk for Brain-Related Disorders

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