Integrative transcriptome network analysis of iPSC-derived neurons from schizophrenia and schizoaffective disorder patients with 22q11.2 deletion

Mingyan Lin, Erika Pedrosa, Anastasia Hrabovsky, Jian Chen, Benjamin R. Puliafito, Stephanie R. Gilbert, Deyou Zheng, Herbert M. Lachman

Research output: Contribution to journalArticle

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Abstract

Background: Individuals with 22q11.2 Deletion Syndrome (22q11.2 DS) are a specific high-risk group for developing schizophrenia (SZ), schizoaffective disorder (SAD) and autism spectrum disorders (ASD). Several genes in the deleted region have been implicated in the development of SZ, e.g., PRODH and DGCR8. However, the mechanistic connection between these genes and the neuropsychiatric phenotype remains unclear. To elucidate the molecular consequences of 22q11.2 deletion in early neural development, we carried out RNA-seq analysis to investigate gene expression in early differentiating human neurons derived from induced pluripotent stem cells (iPSCs) of 22q11.2 DS SZ and SAD patients. Methods: Eight cases (ten iPSC-neuron samples in total including duplicate clones) and seven controls (nine in total including duplicate clones) were subjected to RNA sequencing. Using a systems level analysis, differentially expressed genes/gene-modules and pathway of interests were identified. Lastly, we related our findings from in vitro neuronal cultures to brain development by mapping differentially expressed genes to BrainSpan transcriptomes. Results: We observed ~2-fold reduction in expression of almost all genes in the 22q11.2 region in SZ (37 genes reached p-value < 0.05, 36 of which reached a false discovery rate < 0.05). Outside of the deleted region, 745 genes showed significant differences in expression between SZ and control neurons (p < 0.05). Function enrichment and network analysis of the differentially expressed genes uncovered converging evidence on abnormal expression in key functional pathways, such as apoptosis, cell cycle and survival, and MAPK signaling in the SZ and SAD samples. By leveraging transcriptome profiles of normal human brain tissues across human development into adulthood, we showed that the differentially expressed genes converge on a sub-network mediated by CDC45 and the cell cycle, which would be disrupted by the 22q11.2 deletion during embryonic brain development, and another sub-network modulated by PRODH, which could contribute to disruption of brain function during adolescence. Conclusions: This study has provided evidence for disruption of potential molecular events in SZ patient with 22q11.2 deletion and related our findings from in vitro neuronal cultures to functional perturbations that can occur during brain development in SZ.

Original languageEnglish (US)
Article number105
JournalBMC Systems Biology
Volume10
Issue number1
DOIs
StatePublished - Nov 15 2016

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Induced Pluripotent Stem Cells
Stem Cells
Network Analysis
Gene Expression Profiling
Electric network analysis
Stem cells
Psychotic Disorders
Deletion
Neurons
Disorder
Neuron
Schizophrenia
Genes
Gene
Brain
DiGeorge Syndrome
Transcriptome
Cell Cycle
RNA
Clone

ASJC Scopus subject areas

  • Structural Biology
  • Modeling and Simulation
  • Molecular Biology
  • Computer Science Applications
  • Applied Mathematics

Cite this

Integrative transcriptome network analysis of iPSC-derived neurons from schizophrenia and schizoaffective disorder patients with 22q11.2 deletion. / Lin, Mingyan; Pedrosa, Erika; Hrabovsky, Anastasia; Chen, Jian; Puliafito, Benjamin R.; Gilbert, Stephanie R.; Zheng, Deyou; Lachman, Herbert M.

In: BMC Systems Biology, Vol. 10, No. 1, 105, 15.11.2016.

Research output: Contribution to journalArticle

Lin, Mingyan ; Pedrosa, Erika ; Hrabovsky, Anastasia ; Chen, Jian ; Puliafito, Benjamin R. ; Gilbert, Stephanie R. ; Zheng, Deyou ; Lachman, Herbert M. / Integrative transcriptome network analysis of iPSC-derived neurons from schizophrenia and schizoaffective disorder patients with 22q11.2 deletion. In: BMC Systems Biology. 2016 ; Vol. 10, No. 1.
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AU - Chen, Jian

AU - Puliafito, Benjamin R.

AU - Gilbert, Stephanie R.

AU - Zheng, Deyou

AU - Lachman, Herbert M.

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