Integrative Analysis Extracts a Core ceRNA Network of the Fetal Hippocampus With Down Syndrome.

Shengran Wang,Shasha Bian,Keyue Ding,Qingqing Wang,Jianqin Gu,Weili Shi,Litao Qin,Bingtao Hao,Xia Tang,Zhaokun Wang,Shixiu Liao,Xin Wang

doi:10.3389/fgene.2020.565955

Shengran Wang, Shasha Bian + Show 10 more

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https://doi.org/10.3389/fgene.2020.565955

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Abstract

Accumulating evidence suggests that circular RNAs (circRNAs)—miRNA–mRNA ceRNA regulatory network—may play an important role in neurological disorders, such as Alzheimer’s disease (AD). Interestingly, neuropathological changes that closely resemble AD have been found in nearly all Down syndrome (DS) cases > 35 years. However, few studies have reported circRNA transcriptional profiling in DS cases, which is caused by a chromosomal aberration of trisomy 21. Here, we characterized the expression profiles of circRNAs in the fetal hippocampus of DS patients (n = 8) and controls (n = 6) by using microarray. MiRNA, mRNA expression profiling of DS from our previous study and scRNA-seq data describing normal fetal hippocampus development (GEO) were also integrated into the analysis. The similarity between circRNAs/genes with traits/cell-types was calculated by weighted correlation network analysis (WGCNA). miRanda and miRWalk2 were used to predict ceRNA network interactions. We identified a total of 7,078 significantly differentially expressed (DE) circRNAs, including 2,637 upregulated and 4,441 downregulated genes, respectively. WGCNA obtained 15 hub circRNAs and 6 modules with cell type–specific expression patterns among scRNA-seq data. Finally, a core ceRNA network was constructed by 14 hub circRNAs, 17 DE miRNA targets and 245 DE mRNA targets with a cell type–specific expression pattern annotation. Known functional molecules in DS or neurodegeneration (e.g., miR-138, OLIG1, and TPM2) were also included in this network. Our findings are the first to delineate the landscape of circRNAs in DS and the first to effectively integrate ceRNA regulation with scRNA-seq data. These data may provide a valuable resource for further research on the molecular mechanisms or therapeutic targets underlying DS neuropathy.

Highlights

Down syndrome (DS) is one of the leading causes of congenital intellectual disability and cognitive impairment due to a naturally occurring extra copy of chromosome 21, i.e., trisomy 21 (Zhao Y. et al, 2017)
The expression profiles of circRNAs were characterized in the fetal hippocampus of eight DS patients and six diploid embryos
3www.alzdata.org ceRNA Network of DS Hippocampus expression levels of circRNAs was similar between the DS patients and diploid embryos, and differentially expressed (DE) circRNAs were identified (Supplementary Figures S2A–C)

Summary

Introduction

Down syndrome (DS) is one of the leading causes of congenital intellectual disability and cognitive impairment due to a naturally occurring extra copy of chromosome 21, i.e., trisomy 21 (Zhao Y. et al, 2017). Pathological changes of the neurogenesis impairment, such as hypocellularity in the hippocampus, were significant causes of the functional alteration observed in DS patients (Guidi et al, 2008). The epigenetic changes mediated by miRNAs in the hippocampus have been demonstrated in DS, e.g., miR-155 targeting CFH may protect neurons from axonal injury (Brás et al, 2018). More attention has been paid to a new class of noncoding RNA [i.e., circular RNAs (circRNAs) (Li et al, 2018)] with multiple molecular functions, such as competing with linear RNAs in the splicing, deriving pseudogenes, working as endogenous miRNA sponges (Jiang et al, 2019), and encoding proteins (Yang et al, 2018; Wang et al, 2019). CiRS-7 may act as an miRNA-7 sponge that is involved in a significantly dysregulated circuit of ciRS-7-miRNA-7-UBE2A in AD (Zhao et al, 2016)

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