- Biclustering of transcriptome sequencing data reveals human tissue-specific. - circular RNAs. - Background: Emerging evidence has been experimentally confirmed the tissue-specific expression of circRNAs (circRNAs). - Global identification of human tissue-specific circRNAs is crucial for the functionality study, which facilitates the discovery of circRNAs for potential diagnostic biomarkers.. - Results: In this study, circRNA back-splicing junctions were identified from 465 publicly available transcriptome sequencing samples. - The result provides thousands of newly identified human tissue-specific circRNAs.. - Conclusions: This result suggests that expression of circRNAs is not prompted by random splicing error but serving molecular functional roles. - We also identified circRNAs enriched within circulating system, which, along with identified tissue-specific circRNAs, can serve as potential diagnostic biomarkers.. - Circular RNAs (circRNAs) are a type of long non-coding RNAs, whose 3′ and 5′ ends joined into a single strand circular form. - Emerging evidence indicates the tissue-specific circRNAs play crucial roles in post-transcriptional level. - Biogenesis of circRNAs was found. - competing with the mRNAs of the host gene. - Global identifi- cation of human tissue-specific circRNAs is crucial for the study of circRNAs functionality.. - The junctions between the 3′ and 5′ ends of the cir- cRNAs have been referred as back-splicing junctions.. - To discover human tissue-specific circRNAs, we collected 465 human transcriptome sequencing runs and applied the established pipeline. - Expression level of circRNAs was estimated using the normalized counts of. - Full list of author information is available at the end of the article. - 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0. - The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.. - reads spanning the back-splicing junctions [7]. - From the result 66 bicluster models, we found a huge portion of circRNAs ex- press only in the specific tissue type. - This result suggests that expression of circRNAs is not prompted by random splicing error but serving molecular functional roles. - We also identified circRNAs enriched within circulating sys- tem, which, along with identified tissue-specific circRNAs, can serve as potential diagnostic biomarkers.. - A total 148,095 unique back-splicing junctions were identified from the selected transcriptome sequencing runs. - Each of the junction site satisfy the threshold de- fined in the find_circ scripts [4, 9], as provided in the (Additional file 1). - Back-splicing junctions with only one spliced. - The result of the biclustering reflects that the expression profiles of circRNAs are under tissue-specific regulation. - A network view of the identified tissue-specific circRNAs is illustrated in Fig. - It had been assumed that since the exon originated cir- cRNAs does not go through polyadenylation process after transcribed and spliced, they cannot be identified in the ploy-A enriched RNA-Seq data. - However in sev- eral recent studies circRNAs were identified in poly-A enriched RNA-Seq data sets, this could be due to the fact that some circular isoforms of the gene are adenine-rich. - In this study, we discovered 24,589 unique back-splicing junctions from the 376 selected poly-A enriched RNA-Seq runs. - One of the pivotal circRNA cdr1as [3, 4], which was proven to be nature miRNA miR-7 sponge, was found in 107 of our selected runs.. - 1 Network summary of the tissue-specific circRNAs. - The circular nodes in this graph represents amount of grouped back-splicing junctions.. - Red nodes represent tissue-specific circRNAs, while blue nodes represent circRNAs enriched in multiple tissue types. - Compared with human circRNAs reported in 22 recent studies we found 5680 identified cir- cRNAs back-splicing junctions has been reported in other studies. - The remaining 92,015 unique back- splicing junctions are considered as novel circRNA can- didates. - Isoform annotation and the expression profiling can be found in the data base CircNet [30].. - Tissue-specific circRNAs. - 1, the biclustering result provides thousands of tissue-specific expressed circRNAs. - The nodes containing lower than 10 circRNAs, or connects to more than 3 types of tissues were hidden in the graph.. - Some groups of circRNAs express in multiple types of tissues with close correlated function. - For ex- ample, the 332 circRNAs grouped with bowel, colon and large intestine might have potential physiological roles in the digest system, while the 243 circRNAs enriched in prostate and thyroid might correlate with male re- producing or development. - The tissue-specific circRNAs is available in (Additional file 3).. - Based on the result of the gene-set enrichment analysis, we found that host genes of the brain-specific circRNAs are specially enriched with synapse-associated GO terms [32], as listed in Table 1. - Through this study we hypothesize that these brain-specific circRNAs participate in the neuron development and synaptic functions. - The back-splicing. - Potential diagnostic biomarkers revealed from the results of the biclustering. - Besides the tissue specificity of human circRNAs, puta- tive diagnostic biomarkers can be discovered from the bicluster models. - We found 607 back-splicing junctions and cancer skin/prostate samples were clustered into the same bicluster (SD10_10.txt from Additional file 2).. - Samples with close conditions originated from the same tissue types were biclustered with back-spicing junctions, suggesting that circRNAs originated from these back- splicing junctions express specifically to the disease con- dition as well as tissue type. - These back-splicing junction sites and the related conditions are summarized in Table 2. - In this study, we identified the potential tissue specific circRNA through conducting biclustering on expression profiles of circRNA across multiple human tissue sam- ples. - First of all, RNA-Seq data set collected in this study are retroactive sourced. - Without accurate annota- tion of the full-length sequence of circRNA, this kind of measurement can be limited. - Finally, the gene set en- richment conducted in this study was based on the genes locus that intersect with back spliced junction sites. - This analysis was based on the assumption that functions of circRNAs correlate with the functions of back spliced junction sites overlapped genes. - Weather tissue specific genes correlate with the biogenesis of tissue specific circRNA Is also an ongoing research Table 1 Summary of the putative biomarkers. - GO:0015630|microtubule cytoskeleton 34 1.09E-11 The GO term enrichment of back spliced junction sites clustered into brain is summarized in this table. - Table 2 Summary of the putative biomarkers. - The number of back-splicing junctions clustered into tissue and condition models is summarized in this table. - Further analysis of the issue specific circRNA locus correlation with known tissue specific genes should be conducted in the near future.. - From the result 66 bicluster models, we found a huge por- tion of circRNAs express only in the specific tissue type.. - We also identified circRNAs enriched within circulating system, which, along with identified tissue-specific circRNAs, can serve as potential diagnostic biomarkers after sufficient experiment verification as well as population studies.. - Selection of the RNA-Seq runs was made on purpose of covering as many different conditions as possible. - Quality control of the sequence reads was conducted through the NGS QC toolkit [35]. - The algorithm referred as find_circ [4, 9] was applied to detect back-splicing junctions. - To normalize the amount of the normalized sequence reads spanning the junctions, a concept of spliced reads per billion mapping (SRPBM) was applied [7]. - 2 Summary of the data analysis process. - The data analysis process conducted in this study is summarized in this flowchart. - Gene sets enrichment of the circRNA host genes was con- ducted through DAVID [40]. - Back spliced junction sites clustered into models containing only one types of tissue were considered as tissue-specific circRNAs originated.. - Additional file 1: One hundred forty-eight thousand ninety-five unique back-splicing junctions were identified from the selected transcriptome sequencing runs. - Each of the junction site satisfy the threshold defined in the find_circ scripts. - (RAR 1442 kb) Additional file 3: The tissue-specific circRNAs. - (XLSX 426 kb) Additional file 4: The back-splicing junction sites were enriched into these 9 gene groups. - Additional file 5: Collection of circRNAs can serve as potential diagnostic biomarkers. - The research reported in this paper was mainly supported by “ Aiming for the Top University Program ” of the National Chiao Tung University and Ministry of Education, Taiwan, R.O.C.. - The full contents of the supplement are available online at https://bmcgenomics.biomedcentral.com/articles/supplements/. - All authors participated in the audition. - and revision of the manuscript. - Circular RNAs are the predominant transcript Isoform from hundreds of human genes in diverse cell types. - Circular RNAs are a large class of animal RNAs with regulatory potency. - Circular RNAs are abundant, conserved, and associated with ALU repeats. - circBase: a database for circular RNAs.. - Expanded identification and characterization of mammalian circular RNAs. - Circular RNA expression: its potential regulation and function.. - Identification and characterization of hypoxia-regulated endothelial circular RNA. - The RNA binding protein quaking regulates formation of circRNAs. - Identification and characterization of circular RNAs as a new class of putative biomarkers in human blood. - Circular RNA enrichment in platelets is a signature of transcriptome degradation. - Specific identification and quantification of circular RNAs from sequencing data. - Diverse alternative back-splicing and alternative splicing landscape of circular RNAs. - Circular RNA profile in gliomas revealed by identification tool UROBORUS. - Tracing the expression of circular RNAs in human pre-implantation embryos.. - Cell-type specific features of circular RNA expression. - Circular RNAs in the mammalian brain are highly abundant, conserved, and dynamically expressed. - CircNet: a database of circular RNAs derived from. - Analysis of the human tissue-specific expression by genome-wide integration of transcriptomics and antibody-based proteomics. - Neural circular RNAs are derived from synaptic genes and regulated by development and plasticity
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