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

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

doi:10.1038/s41537-019-0071-2

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.

Highlights

Oligodendrocytes (OLG) dysfunction and myelin deficit are well-established contributors to the pathophysiology of schizophrenia (SZ)
Neat1 is associated with OLG/myelin-related gene expression signature in an independent myelin-associated mouse model The genes affected in Neat1-/- mice that were closely associated with OLG markers (Fig. 4a) and differentiation of OLG (magenta module (Fig. 4a, b)) showed similar reduction across the 14 accessed cerebrocortical regions in individuals with SZ, suggesting inhibition of OLG differentiation in SZ (Table 1)
The main findings of this study are as follows: (i) NEAT1 is downregulated in multiple brain regions of individuals with SZ and is among the most affected genes in SZ; (ii) murine Neat1 deletion affected multiple genes involved in OLG cell differentiation accompanied by reduced population of OLG-lineage cells in the frontal cortex of Neat1-/- mice; (iii) RNA-seq of human chromatin isolates purified with NEAT1 antisense probes (ChiRP) identifies multiple OLG-specific RNAs, suggesting that NEAT1 is an epigenetic regulator of OLG gene expression; (iv) Neat1 loss is associated with reduced nuclear retention of the RNA-binding protein, Qki-5, and highlights additional mechanisms by which NEAT1 may regulate OLG-specific differentiation

Summary

INTRODUCTION

Oligodendrocytes (OLG) dysfunction and myelin deficit are well-established contributors to the pathophysiology of schizophrenia (SZ) (reviewed in ref. 1). Neat is associated with OLG/myelin-related gene expression signature in an independent myelin-associated mouse model The genes affected in Neat1-/- mice that were closely associated with OLG markers (Fig. 4a) and differentiation of OLG (magenta module (Fig. 4a, b)) showed similar reduction across the 14 accessed cerebrocortical regions in individuals with SZ, suggesting inhibition of OLG differentiation in SZ (Table 1). To explore the association of Neat with OLG gene expression signatures further, we measured mRNA levels of Neat and OLG-specific markers in the frontal cortex and white matter of demyelinating “quaking” Qke528 mice (Fig. 4c). Comparison of gene expression changes from frontal cortex of Neat1-/- and control mice (Fig. 4c) showed significant (Student’s two-tailed t-test; ps ≤ 0.05) reduction of OLG-specific genes (Olig, Cnp, Mag, and Sox10) by qPCRs and validated by RNA-seq (Olig, Mag, Cnp; Table 1 and S12).

DISCUSSION

Findings

Ethics statement and brain specimens