title: Common developmental genome deprogramming in schizophrenia - Role of Integrative Nuclear FGFR1 Signaling (INFS).
abstract: The watershed-hypothesis of schizophrenia asserts that over 200 different mutations dysregulate distinct pathways that converge on an unspecified common mechanism(s) that controls disease ontogeny. Consistent with this hypothesis, our RNA-sequencing of neuron committed cells (NCCs) differentiated from established iPSCs of 4 schizophrenia patients and 4 control subjects uncovered a dysregulated transcriptome of 1349 mRNAs common to all patients. Data reveals a global dysregulation of developmental genome, deconstruction of coordinated mRNA networks, and the formation of aberrant, new coordinated mRNA networks indicating a concerted action of the responsible factor(s). Sequencing of miRNA transcriptomes demonstrated an overexpression of 16 miRNAs and deconstruction of interactive miRNA-mRNA networks in schizophrenia NCCs. ChiPseq revealed that the nuclear (n) form of FGFR1, a pan-ontogenic regulator, is overexpressed in schizophrenia NCCs and overtargets dysregulated mRNA and miRNA genes. The nFGFR1 targeted 54% of all human gene promoters and 84.4% of schizophrenia dysregulated genes. The upregulated genes reside within major developmental pathways that control neurogenesis and neuron formation, whereas downregulated genes are involved in oligodendrogenesis. Our results indicate (i) an early (preneuronal) genomic etiology of schizophrenia, (ii) dysregulated genes and new coordinated gene networks are common to unrelated cases of schizophrenia, (iii) gene dysregulations are accompanied by increased nFGFR1-genome interactions, and (iv) modeling of increased nFGFR1 by an overexpression of a nFGFR1 lead to up or downregulation of selected genes as observed in schizophrenia NCCs. Together our results designate nFGFR1 signaling as a potential common dysregulated mechanism in investigated patients and potential therapeutic target in schizophrenia.
authors.affiliation: Department of Pathology and Anatomical Sciences, State University of New York at Buffalo, Buffalo, NY, USA; Western New York Stem Cell Culture and Analysis Center, State University of New York at Buffalo, Buffalo, NY, USA.
authors.forename: S T
authors.initials: ST
authors.lastname: Narla
authors.affiliation: Department of Pathology and Anatomical Sciences, State University of New York at Buffalo, Buffalo, NY, USA.
authors.forename: Y-W
authors.initials: YW
authors.lastname: Lee
authors.affiliation: Department of Pathology and Anatomical Sciences, State University of New York at Buffalo, Buffalo, NY, USA; Western New York Stem Cell Culture and Analysis Center, State University of New York at Buffalo, Buffalo, NY, USA.
authors.forename: C A
authors.initials: CA
authors.lastname: Benson
authors.affiliation: Department of Pathology and Anatomical Sciences, State University of New York at Buffalo, Buffalo, NY, USA.
authors.forename: P
authors.initials: P
authors.lastname: Sarder
authors.affiliation: Icahn School of Medicine at Mount Sinai, Departments of Psychiatry and Neuroscience, New York, NY, USA.
authors.forename: K J
authors.initials: KJ
authors.lastname: Brennand
authors.affiliation: Department of Pathology and Anatomical Sciences, State University of New York at Buffalo, Buffalo, NY, USA; Western New York Stem Cell Culture and Analysis Center, State University of New York at Buffalo, Buffalo, NY, USA.
authors.forename: E K
authors.initials: EK
authors.lastname: Stachowiak
authors.affiliation: Department of Pathology and Anatomical Sciences, State University of New York at Buffalo, Buffalo, NY, USA; Western New York Stem Cell Culture and Analysis Center, State University of New York at Buffalo, Buffalo, NY, USA. Electronic address: mks4@buffalo.edu.
authors.forename: M K
authors.initials: MK
authors.lastname: Stachowiak
mesh_terms: D000328:Adult; D002454:Cell Differentiation; D002478:Cells, Cultured; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000235:genetics*; D053263:Gene Regulatory Networks; D016678:Genome / Q000235:genetics*; D023281:Genomics; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000502:physiology; D008297:Male; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D008954:Models, Biological; D009154:Mutation / Q000235:genetics*; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000235:genetics* / Q000378:metabolism*; D051881:Receptor, Notch1 / Q000378:metabolism; D012559:Schizophrenia / Q000235:genetics* / Q000473:pathology; D015398:Signal Transduction / Q000235:genetics*; D059467:Transcriptome; D055815:Young Adult
chemical_list: D035683:MicroRNAs; C497762:Notch1 protein, mouse; D051881:Receptor, Notch1; C496348:FGFR1 protein, human; D051496:Receptor, Fibroblast Growth Factor, Type 1
keywords: Developmental hypothesis; Fibroblast Growth Factor Receptor 1; Genome regulation; Schizophrenia; miRNA