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 reveal global dysregulation of developmental genome, deconstruction of coordinated mRNA, and 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 coordinated 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.

Functional analysis of evolutionary human methylated regions in schizophrenia patients

“…FGFR1 has been previously implicated in schizophrenia [51,52]. DMR526 does not overlap with any genes but may be involved in long-range regulation of MARK3 determined through Hi-C genome-wide contact matrix ( Supplementary Figure S6), When looking at the blood samples [15] from patients with schizophrenia, we fail to find evidence of any methylation variation in these evolutionary DMRs.…”

Modeling schizophrenia pathogenesis using patient-derived induced pluripotent stem cells (iPSCs)

“…It remains to be determined how the NPC migration deficit contributes to the pathogenesis of SCZ and whether correction of the migration deficit could be a novel preventive therapeutic target for SCZ. Disruption of gene pathways that are critical for neurodevelopment [48,52] comports well with the developmental hypothesis of SCZ pathogenesis.…”

“…Subject selection criteria vary in these studies, spanning from specific genetic abnormalities like CNVs such as 22q11.2 deletion [38–40], 15q11.2 deletion [41] or CNTNAP2 deletion [42] and mutations such as DISC1 mutation [43,44] to SCZ patients with no identified genetic risk factor drawn from clinical populations [45–48]. Childhood onset SCZ (COS) [49], has also been studied since COS exhibits more severe psychopathology as compared to adult onset SCZ and thus would likely have a more robust cellular phenotype.…”

“…In these studies, the neural populations generated, range from neural progenitor cells (NPC) [41–43,45,46,48,49,52] to mixed neural populations [38–40,47,53] and to more specific neural subtypes such as highly enriched glutamatergic neurons [44]. These iPSC-derived neural populations recapitulate the normal developmental time frame and more closely resemble fetal neural progenitors and neuronal populations, suitable for analysis of developmental abnormalities.…”

“…For NPCs derived from idiopathic SCZ cohort, increased expression of the Wnt signaling pathway [52], abnormal nuclear FGFR1 pathway [48], increased protein translation [45], neuronal migration deficits and oxidative stress [46] have been reported. Topol et al described a molecular substrate of disrupted neuronal migration, decreased mir9 expression, and found that transfection of mir9 reversed the migration deficit [49].…”