Dysregulation of Long Intergenic Non-Coding RNA Expression in the Schizophrenia Brain

Abstract

BACKGROUND: Transcriptomic studies of the brains of schizophrenia (SZ) patients have produced abundant but largely inconsistent findings about the disorder’s pathophysiology. These inconsistencies might stem not only from the heterogeneous nature of the disorder, but also from the unbalanced focus on particular cortical regions and protein-coding genes. Compared to protein-coding transcripts, long intergenic non-coding RNA (lincRNA) display substantially greater brain region and disease response specificity, positioning them as prospective indicators of SZ-associated alterations. Further, a growing understanding of the systemic character of the disorder calls for a more systematic screening involving multiple diverse brain regions.

AIM: We aimed to identify and interpret alterations of the lincRNA expression profiles in SZ by examining the transcriptomes of 35 brain regions.

METHODS: We measured the transcriptome of 35 brain regions dissected from eight adult brain specimens, four SZ patients, and four healthy controls, using high-throughput RNA sequencing. Analysis of these data yielded 861 annotated human lincRNAs passing the detection threshold.

RESULTS: Of the 861 detected lincRNA, 135 showed significant region-dependent expression alterations in SZ (two-way ANOVA, BH-adjusted p <0.05) and 37 additionally showed significant differential expression between HC and SZ individuals in at least one region (post hoc Tukey test, p <0.05). For these 37 differentially expressed lincRNAs (DELs), 88% of the differences occurred in a cluster of brain regions containing axon-rich brain regions and cerebellum. Functional annotation of the DEL targets further revealed stark enrichment in neurons and synaptic transmission terms and pathways.

CONCLUSION: Our study highlights the utility of a systematic brain transcriptome analysis relying on the expression profiles measured across multiple brain regions and singles out white matter regions as a prospective target for further SZ research.

Keywords

schizophrenia / long intergenic non-coding RNA / lincRNA / white matter / transcriptome / brain

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Funding

Russian Science FoundationРоссийский научный фонд(22-15-00474)

RIGHTS & PERMISSIONS

Nguyen T., Efimova O.I., Tokarchuk A.V., Morozova A.Y., Zorkina Y.A., Andreyuk D.S., Kostyuk G.P., Khaitovich P.E.