Common developmental genome deprogramming in schizophrenia - Role of Integrative Nuclear FGFR1 Signaling (INFS)

Area of Science:

• Neuroscience
• Genetics
• Molecular Biology

Background:

• Schizophrenia is hypothesized to stem from distinct genetic mutations converging on common mechanisms controlling disease development.
• Previous research suggests a complex interplay of genetic and molecular factors in schizophrenia etiology.

Purpose of the Study:

• To investigate the molecular underpinnings of schizophrenia using RNA-sequencing and miRNA-sequencing on neuron committed cells (NCCs) derived from induced pluripotent stem cells (iPSCs).
• To identify common dysregulated pathways and potential key regulatory factors in schizophrenia.
• To explore the role of nuclear FGFR1 (nFGFR1) in the observed gene expression changes.

Main Methods:

• RNA-sequencing and miRNA-sequencing of NCCs from schizophrenia patients and healthy controls.
• Chromatin immunoprecipitation sequencing (ChiPseq) to assess nFGFR1 binding to gene promoters.
• In vitro modeling to evaluate the effects of nFGFR1 overexpression on gene expression.

Main Results:

• A common set of 1349 dysregulated mRNAs and 16 overexpressed miRNAs were identified in schizophrenia NCCs.
• Global disruption of developmental gene expression, mRNA networks, and formation of aberrant mRNA networks were observed.
• nFGFR1 was found to be overexpressed and extensively targeted dysregulated genes, particularly those involved in neurogenesis and oligodendrogenesis.
• Overexpression of nFGFR1 mimicked the observed gene dysregulations in NCCs.

Conclusions:

• Schizophrenia exhibits an early, pre-neuronal genomic etiology with common molecular signatures across unrelated patients.
• Increased nFGFR1 signaling is a potential unifying mechanism driving gene dysregulation in schizophrenia.
• nFGFR1 represents a promising therapeutic target for schizophrenia treatment.