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. 2018 Dec 19;10(472):eaat6912.
doi: 10.1126/scitranslmed.aat6912. Epub 2018 Dec 13.

The DGCR5 long noncoding RNA may regulate expression of several schizophrenia-related genes (V体育安卓版)

Qingtuan Meng  1 , Kangli Wang  1 , Tonya Brunetti  2   3 , Yan Xia  1 , Chuan Jiao  1 , Rujia Dai  1 , Dominic Fitzgerald  2 , Amber Thomas  2 , Lindsey Jay  2 , Heather Eckart  2 , Kay Grennan  4 , Yuka Imamura-Kawasawa  5   6 , Mingfeng Li  6 , Nenad Sestan  6 , Kevin P White  2   7 , Chao Chen  8   9 , Chunyu Liu  8   4   10
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The DGCR5 long noncoding RNA may regulate expression of several schizophrenia-related genes

Qingtuan Meng et al. Sci Transl Med. .

"V体育官网" Abstract

A number of studies indicate that rare copy number variations (CNVs) contribute to the risk of schizophrenia (SCZ). Most of these studies have focused on protein-coding genes residing in the CNVs. Here, we investigated long noncoding RNAs (lncRNAs) within 10 SCZ risk-associated CNV deletion regions (CNV-lncRNAs) and examined their potential contribution to SCZ risk. We used RNA sequencing transcriptome data derived from postmortem brain tissue from control individuals without psychiatric disease as part of the PsychENCODE BrainGVEX and Developmental Capstone projects. We carried out weighted gene coexpression network analysis to identify protein-coding genes coexpressed with CNV-lncRNAs in the human brain. We identified one neuronal function-related coexpression module shared by both datasets. This module contained a lncRNA called DGCR5 within the 22q11. 2 CNV region, which was identified as a hub gene. Protein-coding genes associated with SCZ genome-wide association study signals, de novo mutations, or differential expression were also contained in this neuronal module. Using DGCR5 knockdown and overexpression experiments in human neural progenitor cells derived from human induced pluripotent stem cells, we identified a potential role for DGCR5 in regulating certain SCZ-related genes. VSports手机版.

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Conflict of interest statement

Competing interests: K. P V体育ios版. W is President and a shareholder in Tempus Labs, Inc.

Figures

Fig. 1.
Fig. 1.. Study Workflow.
We retrieved annotated lncRNAs mapped to ten SCZ risk-associated CNV deletions (A). We analyzed four human brain transcriptome data sets (BrainGVEX, Developmental Capstone, GTEx, and BrainCloud) from individuals without psychiatric disease. The BrainGVEX (N = 259) and GTEx (N = 101) data sets contained human adult control brains; the Developmental Capstone (N = 37) and BrainCloud (N = 269) data sets contained developing human brains (B). We used WGCNA to identify SCZ-related genes that were coexpressed with the CNV-lncRNAs (C). After identifying hub CNV-lncRNAs from modules related to neuronal functions (D), in vitro experiments were used to validate the predicted regulation of coexpressed SCZ-related genes by hub CNV-lncRNAs (E).
Fig. 2.
Fig. 2.. Functional annotation of CNV-lncRNA coexpression modules.
Modules containing CNV-lncRNAs are represented as horizontal bars with different colors. Neuronal modules (turquoise and blue) from the BrainGVEX data set (human adult control brains, N = 259) (A), and neuronal modules (brown, yellow, and greenyellow) from the Developmental Capstone data set (developing human brains, N = 37) (B) are indicated within the red box. The red dashed line indicates FDR = 0.05. For each module, the top 3 Gene Ontology (GO) terms (FDR < 0.05) are listed on the y axis, and values of -log10(FDR) are shown on the x axis.
Fig. 3.
Fig. 3.. Preservation tests for CNV-lncRNA coexpression modules.
Circles with different colors represent different CNV-lncRNA coexpression modules. The horizontal and vertical axes represent gene number and Zsummary values for each module, respectively. The blue dotted line indicates Zsummary = 2, and the green dotted line indicates Zsummary = 10. Neuronal modules in the BrainGVEX data set (human adult control brains, N = 259) (A) and Developmental Capstone data set (developing human brains, N = 37) (B) are indicated with arrows.
Fig. 4.
Fig. 4.. The CNV-lncRNA DGCR5 in the coexpression module.
Shown is the key driver analysis for the CNV-lncRNA DGCR5 coexpression module from the BrainGVEX data set (human adult control brains, N = 259) (A) and Developmental Capstone data set (developing human brains, N = 37) (B) are. Subsets of SCZ-related genes are indicated in different colors. Sizes of the nodes represent their weighted correlations with DGCR5.
Fig. 5.
Fig. 5.. DGCR5 may regulate expression of the coexpressed SCZ-related genes.
qPCR analysis was used to detect expression changes of SCZ-related genes that coexpressed with DGCR5 after DGCR5 knockdown or overexpression in hNPCs derived from hiPSCs. The blue and red bars represent the DGCR5 knockdown and overexpression groups, respectively; the black bars represent the group used as either negative control for knockdown of DGCR5 and LINC01637, or the empty vector group for overexpression. qPCR analysis was first used to detect expression changes in selected SCZ GWAS and DNM genes (A) and BrainGVEX DEGs and CommonMind DEGs (B) after knockdown of DGCR5 in hNPCs derived from hiPSCs. Positive results from (A) and (B) were further validated in experiments where the control lncRNA LINC01637 was knocked down (C) and DGCR5 was overexpressed (D) in hNPCs derived from hiPSCs. The knockdown and overexpression experiments were conducted in three biological replicates. Data are shown as means ± SEM. Gene expression in the control group was normalized to 1. Two-tailed t test was used for comparison between two groups. P values were adjusted for multiple testing using the Benjamini-Hochberg method. *Padjust < 0.05, **Padjust < 0.01.
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