DYSREGULATED TRANSCRIBED ULTRA-CONSERVED REGIONS (TUCRS) REVEAL COMPETING ENDOGENOUS RNA (CERNA) NETWORK DISRUPTION IN SCHIZOPHRENIA

Schizophrenia has unclear etiology, limited biomarkers, and suboptimal treatments. Current approaches focus on dopaminergic dysfunction, overlooking broader mechanisms. Emerging evidence indicates shared molecular pathways between schizophrenia and cancer. Transcribed ultra-conserved regions (TUCRs), are evolutionarily conserved long non-coding RNAs implicated in cancer and neuronal function, remain unexplored in schizophrenia. We hypothesize that TUCR dysregulation contributes to schizophrenia via competing endogenous RNA (ceRNA) networks affecting neurodevelopmental and synaptic pathways.
To test this hypothesis, TUCRs previously associated with cancer and neuronal processes were systematically identified. Six candidates (uc.38, uc.51, uc.63, uc.84, uc.147, and uc.183) were prioritized and analyzed using miRNA binding prediction and ceRNA network construction to identify downstream mRNA targets and enriched biological processes. This approach enabled rational selection of TUCRs with high regulatory relevance for experimental validation. TUCR expression was quantified in peripheral blood samples from schizophrenia patients and healthy controls, and associations with clinical symptom severity were assessed.
Network analysis revealed interactions with 24 miRNAs regulating 628 experimentally validated mRNAs, including hub genes involved in apoptosis (BCL2), neuroplasticity (BDNF), immune signaling (CD4), RNA processing (SRSF1, PTBP1), ubiquitin-mediated degradation (FBXW7), and cytoskeletal dynamics (TUBB), predominantly expressed in nervous tissue. Experimentally, uc.51, uc.63, and uc.84 were significantly downregulated, while uc.147 and uc.183 were upregulated in schizophrenia (p < 0.05). Positive symptom severity correlated with uc.51 (r = 0.527, p < 0.01) and uc.84 (r = 0.348, p < 0.05).
These findings indicate that TUCR-mediated post-transcriptional regulatory networks are disrupted in schizophrenia, positioning TUCRs as potential biomarkers and mechanistic contributors to disease pathology.