The expression of long noncoding RNA NEAT1 is reduced in schizophrenia and modulates oligodendrocytes transcription

Pavel Katsel, Panos Roussos, Peter Fam, Sonia Khan, Weilun Tan, Tetsuro Hirose, Shinichi Nakagawa, Mikhail V. Pletnikov, Vahram Haroutunian

Research output: Contribution to journalArticlepeer-review

Abstract

Oligodendrocyte (OLG)-related abnormalities have been broadly observed in schizophrenia (SZ); however, the etiology of these abnormalities remains unknown. As SZ is broadly believed to be a developmental disorder, the etiology of the myelin abnormalities in SZ may be related to OLG fate specification during development. Noncoding RNAs (ncRNAs) are an important part of multifaceted transcriptional complexes participating in neurogenic commitment and regulation of postmitotic cell function. The long ncRNA, NEAT1, is a structural component of paraspeckles (subnuclear bodies in interchromatin regions) that may control activity of developmental enhancers of OLG fate specification. Gene expression studies of multiple cortical regions from individuals with SZ showed strong downregulation of NEAT1 levels relative to controls. NEAT1-deficient mice show significant decreases in the numbers of OLG-lineage cells in the frontal cortex. To gain further insight into biological processes affected by NEAT1 deficiency, we analyzed RNA-seq data from frontal cortex of NEAT1 -/- mice. Analyses of differentially expressed gene signature from NEAT1 -/- mice revealed a significant impact on processes related to OLG differentiation and RNA posttranscriptional modification with the underlying mechanisms involving Wnt signaling, cell contact interactions, and regulation of cholesterol/lipid metabolism. Additional studies revealed evidence of co-expression of SOX10, an OLG transcription factor, and NEAT1, and showed enrichment of OLG-specific transcripts in NEAT1 purified chromatin isolates from human frontal cortex. Reduced nuclear retention of quaking isoform 5 in NEAT1 -/- mice shed light on possible mechanism(s) responsible for reduced expression of OLG/myelin proteins and supported the involvement of NEAT1 in oligodendrocyte function.

Original languageEnglish (US)
Article number3
Journalnpj Schizophrenia
Volume5
Issue number1
DOIs
StatePublished - Dec 1 2019

ASJC Scopus subject areas

  • Psychiatry and Mental health

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