Abstract
Circular RNA (circRNA), a novel class of noncoding RNAs, has been used extensively to complement transcriptome remodeling in the central nervous system, although the genomic coverage provided has rarely been studied in intracerebral hemorrhage (ICH) and is limited and fails to provide a detailed picture of the cerebral transcriptome landscape. Here, we described sequencing-based transcriptome profiling, providing comprehensive analysis of cerebral circRNA, messenger RNA (mRNA) and microRNA (miRNA) expression in ICH rats. In the study, male Sprague–Dawley rats were subjected to ICH, and next-generation sequencing of RNAs isolated from non-hemorrhagic (Sham) and hemorrhagic (ICH) rat brain samples collected 7 (early phase) and 28 (chronic phase) days after insults, was conducted. Bioinformatics analysis was performed to determine miRNA binding sites and gene ontology of circRNAs, target genes of miRNAs, as well as biological functions of mRNAs, altered after ICH. These analyses revealed different expression profiles of circRNAs, mRNAs and miRNAs in day-7 and day-28 ICH groups, respectively, compared with the Sham. In addition, the expression signature of circRNAs was more sensitive to disease progression than that of mRNAs or miRNAs. Further analysis suggested two temporally specific circRNA-miRNA-mRNA networks based on the competitive endogenous RNA theory, which had profound impacts on brain activities after ICH. In summary, these results suggested an important role for circRNAs in the pathogenesis of ICH and in reverse remodeling based on self-protection support, providing deep insights into diverse possibilities for ICH therapy through targeting circRNAs.
Highlights
Spontaneous intracerebral hemorrhage (ICH) has been a global burden[1]
These analyses revealed that while the coding and noncoding transcriptomes were each dynamically altered with ICH, circRNA expression profile was more sensitive to hemorrhagic stroke attack when compared with the more comprehensive profiling on cerebral coding (mRNA) and miRNA expression profiles
RNASeq reads first underwent transcriptome reconstruction using Cufflinks, of which 11,620 candidate circRNAs were detected and identified, and 9,625 (82.83%) of which were found to be exonic circRNAs composed of the protein coding exons, 730 (6.28%) were intronic circRNAs derived from intron lariats and 1,265 (10.89%) were intergenic ones that consist of unannotated regions of the gene
Summary
Spontaneous intracerebral hemorrhage (ICH) has been a global burden[1]. Transcriptional profiling for coding and noncoding RNAs has been utilized extensively in ICH to gain new insights into complex disease pathways, to identify biomarkers for better diagnostic and prognostic accuracy, and to examine the impact of therapeutic treatments[2,3,4]. We sought to determine whether a more comprehensive profiling on cerebral coding (mRNA) and noncoding (circRNA and miRNA) transcriptomes, would provide a more complete transcriptional landscape in ICH, and whether these changes were dynamically regulated following disease progresses. The cerebral transcriptional signatures of ICH, on days 7 and 28 post insults, were analyzed and compared with those subjected to sham operations, respectively These analyses revealed that while the coding and noncoding transcriptomes were each dynamically altered with ICH, circRNA expression profile was more sensitive to hemorrhagic stroke attack when compared with the mRNA and miRNA expression profiles. The pathological expression pattern of circRNAs associated with cerebral hemorrhage improved in response to disease development to a greater extent than that of either mRNAs or miRNAs, suggesting a biological role for circRNAs in ICH-induced brain activities. The results presented here provided a transcriptome blueprint to identify novel molecular targets and pathways in ICH, as well as new insights into the mechanisms involved in the brain activities responding to ICH progression
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