Dataset Information

The DPYSL2 gene connects mTOR and schizophrenia.

ABSTRACT: We previously reported a schizophrenia-associated polymorphic CT di-nucleotide repeat (DNR) at the 5'-untranslated repeat (UTR) of DPYSL2, which responds to mammalian target of Rapamycin (mTOR) signaling with allelic differences in reporter assays. Now using microarray analysis, we show that the DNR alleles interact differentially with specific proteins, including the mTOR-related protein HuD/ELAVL4. We confirm the differential binding to HuD and other known mTOR effectors by electrophoretic mobility shift assays. We edit HEK293 cells by CRISPR/Cas9 to carry the schizophrenia risk variant (13DNR) and observe a significant reduction of the corresponding CRMP2 isoform. These edited cells confirm the response to mTOR inhibitors and show a twofold shortening of the cellular projections. Transcriptome analysis of these modified cells by RNA-seq shows changes in 12.7% of expressed transcripts at a false discovery rate of 0.05. These transcripts are enriched in immunity-related genes, overlap significantly with those modified by the schizophrenia-associated gene, ZNF804A, and have a reverse expression signature from that seen with antipsychotic drugs. Our results support the functional importance of the DPYSL2 DNR and a role for mTOR signaling in schizophrenia.

SUBMITTER: Pham X

PROVIDER: S-EPMC5314117 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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The DPYSL2 gene connects mTOR and schizophrenia.

Pham X X Song G G Lao S S Goff L L Zhu H H Valle D D Avramopoulos D D

Translational psychiatry 20161101 11

We previously reported a schizophrenia-associated polymorphic CT di-nucleotide repeat (DNR) at the 5'-untranslated repeat (UTR) of DPYSL2, which responds to mammalian target of Rapamycin (mTOR) signaling with allelic differences in reporter assays. Now using microarray analysis, we show that the DNR alleles interact differentially with specific proteins, including the mTOR-related protein HuD/ELAVL4. We confirm the differential binding to HuD and other known mTOR effectors by electrophoretic mob ...[more]

PMID: 27801893

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Project description:Patients with bipolar disorder have a higher risk of suicide than the general population. This study aimed to explore the correlation between suicide and gene methylation, as screened by genome-wide scanning, in children and adolescents with bipolar disorder. A total of 45 children and adolescents with bipolar disorder were divided into a suicidal ideation group (n = 41), a non-suicidal ideation group (n = 4), a low-risk group (n = 12), and a middle-to-high-risk group (n = 33). A pre-experiment was conducted on the suicidal ideation (n = 6) and non-suicidal ideation groups (n = 4). Blood samples were scanned using an Illumina HD 850K microarray, and methylation levels were analysed. Differential methylation sites among the sample groups were screened from the original data, and genes related to suicide were identified. Methylation of the ABI3BP and DPYSL2 genes was detected by pyrophosphate sequencing and statistically analysed. There was a significant difference in age between the low- and middle-risk groups. The results of GO analysis for the suicidal ideation and non-suicidal ideation groups showed that the differential methylation sites were mainly involved in the interferon-γ-mediated signalling pathway, with the main signalling pathways being the inflammatory bowel disease (IBD) pathway and type 1 diabetes mellitus (T1DM) pathway. There were significant differences in the methylation of ABI3BP, HLA-DQB1, HLA-DRB1, AUTS2, SP3, NINJ2, DPYSL2, and other genes between the suicidal and non-suicidal ideation groups. There was also a statistically significant difference in the gene methylation levels between the two groups. However, there was no significant difference in the degree of methylation of the ABI3BP and DPYSL2 genes between the low- and middle-to-high-risk groups. These results suggest that suicidal ideation is correlated with the methylation levels of differentially methylated genes in children with bipolar disorder. However, the severity of suicide risk in paediatric patients with bipolar disorder may not be correlated with the degree of methylation of the ABI3BP and DPYSL2 genes. Therefore, further validation was required.

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The DPYSL2 gene connects mTOR and schizophrenia.

Publications

The DPYSL2 gene connects mTOR and schizophrenia.

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