Integrated analysis of differentially expressed genes and construction of a competing endogenous RNA network in human Huntington neural progenitor cells

Xiaoping Tan,Yang Liu,Taiming Zhang,Shuyan Cong

doi:10.1186/s12920-021-00894-2

Abstract

BackgroundHuntington's disease (HD) is one of the most common polyglutamine disorders, leading to progressive dyskinesia, cognitive impairment, and neuropsychological problems. Besides the dysregulation of many protein-coding genes in HD, previous studies have revealed a variety of non-coding RNAs that are also dysregulated in HD, including several long non-coding RNAs (lncRNAs). However, an integrated analysis of differentially expressed (DE) genes based on a competing endogenous RNA (ceRNA) network is still currently lacking.MethodsIn this study, we have systematically analyzed the gene expression profile data of neural progenitor cells (NPCs) derived from patients with HD and controls (healthy controls and the isogenic controls of HD patient cell lines corrected using a CRISPR-Cas9 approach at the HTT locus) to screen out DE mRNAs and DE lncRNAs and create a ceRNA network. To learn more about the possible functions of lncRNAs in the ceRNA regulatory network in HD, we conducted a functional analysis of Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) and established a protein–protein interaction (PPI) network for mRNAs interacting with these lncRNAs.ResultsWe identified 490 DE mRNAs and 94 DE lncRNAs, respectively. Of these, 189 mRNAs and 20 lncRNAs were applied to create a ceRNA network. The results showed that the function of DE lncRNAs mainly correlated with transcriptional regulation as demonstrated by GO analysis. Also, KEGG enrichment analysis showed these lncRNAs were involved in tumor necrosis factor, calcium, Wnt, and NF-kappa B signaling pathways. Interestingly, the PPI network revealed that a variety of transcription factors in the ceRNA network interacted with each other, suggesting such lncRNAs may regulate transcription in HD by controlling the expression of such protein-coding genes, especially transcription factors.ConclusionsOur research provides new clues for uncovering the mechanisms of lncRNAs in HD and can be used as the focus for further investigation.

Highlights

Huntington’s disease (HD) is one of the most common polyglutamine disorders, leading to progressive dyskinesia, cognitive impairment, and neuropsychological problems
Identification of differentially expressed genes Compared with the control group (CAG33 and HD-C#1, 2), a total of 94 DE long non-coding RNAs (lncRNAs) (49 up-regulated, 45 downregulated) and 490 DE mRNAs (229 up-regulated, 261 down-regulated) were found in HD cell lines with 180 CAG repeats by differentially expression analysis
The strength of differential gene expression was shown in the form of volcano plots, and the top 20 up/down-regulated DE lncRNAs and mRNAs were represented by heatmaps, respectively (Fig. 2)

Summary

Introduction

Huntington’s disease (HD) is one of the most common polyglutamine disorders, leading to progressive dyskinesia, cognitive impairment, and neuropsychological problems. The DNA of healthy persons contains a region of less than 36 CAG repeats that encodes a polyglutamine (polyQ) tract in the huntingtin gene. An extension in the length of the polyQ tract at the N-terminal of the mutant huntingtin protein (mutHTT), encoded by an abnormal HTT gene containing an expansion of CAG repeats (> 36 in length), changes the conformation of mutHTT and leads to intracellular protein aggregates [2]. Carriers with longer CAG repeats of HTT exhibit different severities of HD, depending on the unusual length of CAG repeats [3] How this pure mutant of the ubiquitously expressed protein leads to specific neurodegeneration is, unclear

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Conclusion