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Comprehensive Circular RNA Profiling Reveals That Circular RNA100783 Is Involved in Chronic CD28-associated CD8(+)T Cell Ageing

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Comprehensive Circular RNA Profiling Reveals That Circular RNA100783 Is Involved in Chronic CD28-associated CD8(+)T Cell Ageing

Yu-Hong Wang et al. Immun Ageing.

Abstract

Background: Ageing brings about the gradual deterioration of the immune system, also known as immunosenescence. The role of non-coding circular RNA in immunosenescence is under studied. Using circular RNA microarray data, we assembled Comparison groups (C1, C2, C3 and C4) that allowed us to compare the circular RNA expression profiles between CD28(+)CD8(+) T cells and CD28(-)CD8(+) T cells isolated from healthy elderly or adult control subjects. Using a step-wise biomathematical strategy, the differentially-expressed circRNAs were identified in C1 (CD28(+)CD8(+) vs CD28(-)CD8(+)T cells in the elderly) and C4 (CD28(-)CD8(+)T cells in the elderly vs in the adult), and the commonly-expressed circRNA species from these profiles were optimized as immunosenescence biomarkers.

Results: Four overlapping upregulated circular RNAs (100550, 100783, 101328 and 102592) expressed in cross-comparison between C1 and C4 were validated using quantitative polymerase chain reaction. Of these, only circular RNA100783 exhibited significant validation. None of the down-regulated circular RNAs were expressed in the C1 and the C4 cross-comparisons. Therefore, we further predicted circular RNA100783-targeted miRNA-gene interactions using online DAVID annotation. The analysis revealed that a circular RNA100783-targeted miRNA-mRNA network may be involved in alternative splicing, the production of splice variants, and in the regulation of phosphoprotein expression. Considering the hypothesis of splicing-related biogenesis of circRNAs, we propose that circular RNA100783 may play a role in phosphoprotein-associated functions duringCD28-related CD8(+) T cell ageing.

Conclusions: This study is the first to employ circular RNA profiling to investigate circular RNA-micro RNA interactions in ageing human CD8(+)T cell populations and the accompanying loss of CD28 expression. The overlapping expression of circular RNA100783 may represent a novel biomarker for the longitudinal tracking ofCD28-related CD8(+) T cell ageing and global immunosenescence.

Keywords: Ageing; Biomathematics; CD28; Circular RNA; Microarray; T cell.

Figures

Fig. 1
Fig. 1
The intracellular validation of candidate circRNAs in C1 and C4. Validation of intracellular circRNA was performed using quantitative polymerase chain reaction (qPCR; in triplicate) in three randomly selected RNA samples. The level of intracellular expression of the validated circRNA was the average of these three samples. Prior to determination of the average, the normalized intracellular expression was calculated by the ratio of intracellular expression to microarray expression. Four up-regulated circRNAs (circRNA100550, circRNA100783, circRNA101328 and circRNA102592) and two down-regulated circRNAs with Top-2 Degree (circRNA103741 and circRNA101318) were validated in C1, respectively (a). Simultaneously, the same four up-regulated circRNAs and another two down-regulated circRNAs with Top-2 degree (circRNA104096 and circRNA100264) were validated in C4, respectively (b). Shown from the figure, only circRNA100783 is significantly differentially-expressed in both C1 and C4. Therefore, we supposed circRNA 1000783 might be a potential biomarker of immunosenescence
Fig. 2
Fig. 2
The biomathematical predicted circ000783-targeted circRNA-miRNA-mRNA/gene network. The circ000783-targeted circRNA-miRNA-mRNA/gene network is predicted based on sequence-pairing prediction. There are 73 miRNAs and 1930 genes being targeted in the present circ000783--miRNA-mRNA/gene network (miRNA-dependent cutoff value -0.11, mRNA-dependent cutoff value -0.38). Shown in this figure, miR-125a-5p exhibited the highest degree, followed by miR-33a-5p,miR-33b-5p,miR-580-3p,miR-499a-5p and miR-34b-3p
Fig. 3
Fig. 3
Schematic strategy of pooling circRNA microarray profiles. Eight microarrays are depicted by 8 green circles. After eight microarray profiles were individually acquired, three microarray profiles detecting CD28(+)CD8(+)T cells from three age-dependent elderly subgroups were pooled as Q1,and three microarray profiles detecting CD28(-)CD8(+)T cells from three age-dependent elderly subgroups were pooled as Q2. Consequently, four cross-group comparisons were performed as: Comparison1 (C1:Q1 vs Q2 indicating CD28(+)CD8(+) vs CD28(-)CD8(+) T cells in the elderly); Comparison2 (C2: Q3 vs Q4 indicating CD28(+)CD8(+) vs CD28(-)CD8(+)T cells in the adult); Comparison 3 (C3:Q1 vs Q3 indicating CD28(+)CD8(+)T cells in the elderly vs in the adult); and Comparison4 (C4: Q2 vs Q4 indicating CD28(-)CD8(+)T cells in the elderly vs in the adult)

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