Long non-coding RNAs in ischemic stroke

Abstract

Stroke is one of the leading causes of mortality and disability worldwide. Uncovering the cellular and molecular pathophysiological processes in stroke have been a top priority. Long non-coding (lnc) RNAs play critical roles in different kinds of diseases. In recent years, a bulk of aberrantly expressed lncRNAs have been screened out in ischemic stroke patients or ischemia insulted animals using new technologies such as RNA-seq, deep sequencing, and microarrays. Nine specific lncRNAs, antisense non-coding RNA in the INK4 locus (ANRIL), metastasis-associate lung adenocarcinoma transcript 1 (MALAT1), N1LR, maternally expressed gene 3 (MEG3), H19, CaMK2D-associated transcript 1 (C2dat1), Fos downstream transcript (FosDT), small nucleolar RNA host gene 14 (SNHG14), and taurine-upregulated gene 1 (TUG1), were found increased in cerebral ischemic animals and/or oxygen-glucose deprived (OGD) cells. These lncRNAs were suggested to promote cell apoptosis, angiogenesis, inflammation, and cell death. Our Gene Ontology (GO) enrichment analysis predicted that MEG3, H19, and MALAT1 might also be related to functions such as neurogenesis, angiogenesis, and inflammation through mechanisms of gene regulation (DNA transcription, RNA folding, methylation, and gene imprinting). This knowledge may provide a better understanding of the functions and mechanisms of lncRNAs in ischemic stroke. Further elucidating the functions and mechanisms of these lncRNAs in biological systems under normal and pathological conditions may lead to opportunities for identifying biomarkers and novel therapeutic targets of ischemic stroke.

Fig. 1

The timeline of lncRNA discovery

Fig. 2. Mechanisms of lncRNA functions.

1. Chromosome modification. The lncRNA Xist scaffolds and recruits different kinds of regulatory proteins, such as SMRT/HDAC1-associated repressor protein (SHARP), binds to chromatin by scaffold attachment factor A (SAFA), and promotes histone deacetylation on X chromosomes. Xist also recruits PRCs and triggers methylation of lysine H3K9 and H3k27. 2. Modulating splicing. lncRNA binds to pre-mRNA and blocks the binding of spliceosome to target sequence, results in the formation of splicing variants. 3. Source of miRNA. Many lncRNA genes contain embedded miRNA sequence in its introns or exons, which harbors miRNAs. 4. CeRNA to miRNAs. Some lncRNAs contain complementary binding sites to certain miRNA, which soak up the target miRNA and result in the reduction of miRNA functions in cells. 5. Binding to mRNA and affect its stability or translation

Fig. 3. Function and signal of some ischemic stroke-related lncRNAs.

MCAO middle cerebral artery occlusion, OGD oxygen glucose deprivation, ANRIL antisense non-coding RNA in the INK4 locus, MALAT1 metastasis-associate lung adenocarcinoma transcript 1, TUG1 taurine-upregulated gene 1, MEG3 maternally expressed gene 3, C2dat1 CaMK2D-associated transcript 1, FosDT Fos downstream transcript, SNHG14 small nucleolar RNA host gene 14.