Transcription factor POU3F2 regulates TRIM8 expression contributing to cellular functions implicated in schizophrenia

Area of Science:

• Neuroscience
• Genetics
• Molecular Biology

Background:

• Schizophrenia (SCZ) is a complex neuropsychiatric disorder linked to aberrant gene expression.
• Identifying causal genes and pathogenic mechanisms in SCZ remains a significant challenge.
• The brain-specific transcription factor POU3F2 is a known SCZ risk factor with limited mechanistic understanding.

Purpose of the Study:

• To identify POU3F2 target genes and elucidate its role in SCZ pathogenesis.
• To investigate the regulatory relationship between POU3F2, TRIM8, and SCZ-associated genetic variations.
• To explore the functional consequences of POU3F2 and TRIM8 dysregulation on neural development and synaptic function.

Main Methods:

• Knockdown and RNA-sequencing experiments in human neural progenitor cells (NPCs).
• Luciferase reporter assays and electrophoretic mobility shift assays (EMSA) to assess gene regulation.
• Functional assays examining NPC proliferation, neuronal differentiation, and synaptic transmission.

Main Results:

• POU3F2 was found to regulate 42 SCZ-related genes in human NPCs.
• POU3F2 directly induces TRIM8 expression by binding to the SCZ-associated SNP rs5011218.
• Dysregulation of POU3F2 or TRIM8 impaired NPC neuronal differentiation and excitatory synaptic transmission.

Conclusions:

• POU3F2 regulates TRIM8 expression via the SCZ-associated SNP rs5011218.
• Both POU3F2 and TRIM8 play critical roles in neural development and synaptic function.
• These findings suggest POU3F2 and TRIM8 are involved in the etiology of schizophrenia.