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| Status |
Public on Jul 14, 2023 |
| Title |
Activity-Dependent Transcriptional Program in NGN2+ Neurons Enriched for Genetic Risk for Brain-Related Disorders |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
Genome binding/occupancy profiling by high throughput sequencing
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| Summary |
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.
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| Overall design |
Gene expression (RNA-seq) and open chromatin (ATAC-seq assay) profiles in hiPSC neurons in unstimulated and KCl-stimulated conditions (measured after 1hr and 6hr following membrane depolarization).
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| Web link |
https://labs.icahn.mssm.edu/roussos-lab/ipsc_kcl/
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| Contributor(s) |
Roussos P, Kristen B, Fullard J, Yixuan M, Jaroslav B |
| Citation(s) |
37454787 |
| NIH grant(s) |
| Grant ID |
Grant title |
Affiliation |
Name |
| R01 MH109897 |
Integrated Multiscale Networks in Schizophrenia |
MOUNT SINAI SCHOOL OF MEDICINE |
Panagiotis Roussos |
| R01 MH125246 |
Multiethnic genomic epigenomic and transcriptomic fine-mapping and functional validation analysis of schizophrenia and bipolar disorder risk loci |
MOUNT SINAI SCHOOL OF MEDICINE |
Panagiotis Roussos |
| U01 MH116442 |
The 3D genome in transcriptional regulation across the postnatal life span, with implications for schizophrenia and bipolar disorder |
MOUNT SINAI SCHOOL OF MEDICINE |
Panagiotis Roussos |
| R01 MH101454 |
Contrasting causal microRNAs in forebrain and midbrain COS hiPSC neural cells |
MOUNT SINAI SCHOOL OF MEDICINE |
Kristen Jennifer Brennand |
| R01 MH106056 |
Higher Order Chromatin and Genetic Risk for Schizophrenia |
MOUNT SINAI SCHOOL OF MEDICINE |
Kristen Jennifer Brennand |
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| Submission date |
May 16, 2022 |
| Last update date |
Jul 19, 2023 |
| Contact name |
Jaroslav Bendl |
| E-mail(s) |
jaroslav.bendl@gmail.com
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| Phone |
9173656690
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| Organization name |
Icahn School of Medicine at Mount Sinai
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| Department |
Genetics and Genomics Sciences
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| Lab |
Roussos Lab
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| Street address |
One Gustave L. Levy Place, Department of Genetics and Genomics Sciences, Box 1210
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| City |
New York City |
| State/province |
New York |
| ZIP/Postal code |
10029-6574 |
| Country |
USA |
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| Platforms (1) |
| GPL16791 |
Illumina HiSeq 2500 (Homo sapiens) |
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| Samples (66)
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| Relations |
| BioProject |
PRJNA838554 |
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