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Distinct hippocampal expression profiles of lncRNAs in obese type 2 diabetes mice exhibiting cognitive impairment

ABSTRACT: Cognitive dysfunction has been accepted as a possible complication of type 2 diabetes (T2D), but few studies revealed the potential roles of Long non‑coding RNAs (lncRNAs) in cognitive dysfunction in T2D. The purpose of the current research is to demonstrate the specific expression patterns of lncRNA-mRNA in the hippocampi of T2D db/db mice exhibiting cognitive impairment. In this study, the results from behavioral tests showed that T2D db/db mice displayed short-term and spatial working memory deficits compared to db/m mice. Furthermore, western blot analysis demonstrated that compared with db/m mice, p-GSK3β (ser9) protein levels were markedly elevated in T2D db/db mice (P<0.01). In addition, though not statistically significant, the ratio of p-Tau (Ser396) to Tau 46, α-Synuclein expression and p-GSK3α (ser21) expression were also relatively higher in T2D db/db mice than in db/m mice. The microarray profiling revealed that 75 lncRNAs and 26 mRNAs were obviously dysregulated in T2D db/db mice (>2.0 fold change, P<0.05). GO analysis demonstrated that the differentially expressed mRNAs participated in immune response, extracellular membrane-bounded organelle and extracellular region. KEGG analysis revealed that the differentially expressed mRNAs were mainly involved in one carbon pool by folate, glyoxylate and dicarboxylate metabolism, autophagy, glycine, serine and threonine metabolism and B cell receptor signaling pathway. An lncRNA‑mRNA coexpression network containing 71 lncRNAs and 26 mRNAs was built to investigate the interaction between lncRNA and mRNA. Collectively, these results revealed the differential hippocampal expression profiles of lncRNAs in T2D mice with cognitive dysfunction, and the findings from this study provide new clues for exploring the potential roles of lncRNAs in the pathogenesis of cognitive dysfunction in T2D.

ORGANISM(S): Mus musculus

PROVIDER: GSE151294 | GEO | 2020/06/02

REPOSITORIES: GEO

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Project description:Diabetic nephropathy (DN) as a common complication of diabetes is the primary cause of end-stage renal disease. Sodium butyrate (NaB) is a short chain fatty acid in the metabolic products of intestinal bacterium, and its kidney protective effect has been reported in DN. However, its underlying mechanism remains unclear. The aim of the present study was to investigate the effect of NaB on globe transcriptome changes in DN. In our study, eight-week-male db/db mice which were established DN mice were randomly divided into two groups: the DN+NaB group (DN mice treated with NaB, 5g/kg/day) and the DN group (DN mice treated with saline). Also, the normal db/m mice were used as NC group. Further, blood glucose, body weight, urinary microalbumin and urinary creatinine of mice were measured in three groups. Whole-transcriptome analysis was performed by RNA sequencing (RNA-Seq) to evaluate profiling of lncRNAs and messenger RNAs (mRNAs). Bioinformatic analysis was performed to predict the potential NaB-related lncRNAs and genes in DN. The expressions of lncRNAs and mRNAs were tested by quantitative real-time polymerase chain reaction (qRT-PCR) in renal tissues and mesangial cells treated with NaB. The results of the present study demonstrated that NaB ameliorated renal dysfunction in DN mice. Moreover, RNA-Seq results identified that 17 lncRNAs and 180 mRNAs reversely changed in DN+NaB group when compared with those in DN group. Additionally, the integrated co-expression networks of NaB-related lncRNAs revealed these lncRNAs interacted with 155 key mRNAs. The co-expression networks of mRNAs associated to immune response, antigen processing and presentation and acute inflammatory response to antigenic stimulus. The qRT-PCR data showed that eight mRNAs and seven lncRNAs were dysexpressed by NaB in DN mice and mesangial cell under high glucose condition. Furthermore, the co-expression network of inflammation related lncRNAs and mRNAs demonstrated that those 17 reversed lncRNAs and 37 mRNAs also play essential roles in inflammatory response. In summary, the present study suggests that NaB ameliorates diabetes induced renal dysfunction and regulates transcriptome changes in DN. NaB related lncRNA-mRNA may play roles in the protective effect of NaB in DN.

Project description:Objective: Macrophages play key roles in inflammation and diabetic vascular complications. Emerging evidence implicates long noncoding RNAs (lncRNAs) in inflammation, but their role in macrophage dysfunction associated with inflammatory diabetic complications is unclear and was therefore investigated in this study. Approach and Results: RNA-sequencing and RT-qPCR demonstrated that a lncRNA Dynamin 3 opposite strand (Dnm3os) is upregulated in bone marrow derived macrophages from type2 diabetic (T2D) db/db mice, diet-induced insulin-resistant mice and diabetic ApoE-/- mice, as well as in monocytes from T2D patients relative to controls. Diabetic conditions (High glucose and palmitic acid) induced Dnm3os in mouse macrophages and THP1 human monocytes. Promoter reporter analysis and chromatin-immunoprecipitation (ChIP) assays demonstrated that diabetic conditions induce Dnm3os via NF-kB activation. RNA-FISH and RT-qPCRs of sub-cellular fractions demonstrated nuclear localization and chromatin enrichment of Dnm3os in macrophages. Stable overexpression of Dnm3os in macrophages altered global histone modifications and upregulated inflammation and immune response genes, and phagocytosis. Conversely, siRNA mediated knockdown of Dnm3os attenuated these responses. RNA pull-down assays with macrophage nuclear lysates identified nucleolin and ILF-2 as protein binding partners of Dnm3os, which was further confirmed by RNA-IP and RNA-FISH-immunofluorescence. Furthermore, nucleolin levels were decreased in diabetic conditions, and its knockdown enhanced Dnm3os-induced inflammatory gene expression and histone H3K9-acetylation at their promoters. Conclusions: These results demonstrate novel mechanisms involving upregulation of lncRNA Dnm3os, disruption of its interaction with nucleolin, and epigenetic modifications at target genes that promote macrophage inflammatory phenotype in diabetes. The data could lead to lncRNA-based therapies for inflammatory diabetes complications.

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Distinct hippocampal expression profiles of lncRNAs in obese type 2 diabetes mice exhibiting cognitive impairment

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