| mi RNAs are evolutionarily conserved molecules that can regulate the gene expression within cells. In recent years, with the increasing understanding on mirnas, the mechanism on mirnas transcription, processing and maturation have been clear, and the biological processes and corresponding function that mirna involved in have been widely understood. Also the important roles that mirna play in cell proliferation, differentiation, apoptosis, embryonic, individual development, as well as in various diseases have been thorough understanding. Cancer is growing serious threat to human health and life, so it is particularly important to the study of mirnas because a lot of scientific evidences show that miRNA plays a very important role in the tumors development. Since many miRNAs could stably exist in the body fluids, and are easy to extract and detect, they become potential tumor markers which have inestimable value in the medical. mi RNA clusters define a group of related miRNAs closely localized in the genome with an evolution that remains poorly understood. Among all the mi RNA clusters, stem cell specific miR-302/367 is one of the research hotspot. In this paper, from the perspective of evolutionary, we revealed the function of miRNA clusters and biological processes that their targets participate in, the effect isomiR on target genes, and also predict new miRNA tumor markers depending on variant indexes of isomiR and arm switching by bioinformatics methods. In this process, we collected huge amount of microarray-based and sequencing-based miRNA expression data from several related public databases, and applied and improved existing bioinformatics methods, as well as integrated open source softwares to make it streamlined. So this study describes in detail as following relevant works.1)The miR-302/367 cluster represents a single polycistronic transcript that produces five precursor miRNAs. The cluster is highly expressed and essential for maintenance of human embryonic stem cells. In this paper, we study stem cell specific miR-302/367 cluster from the perspective of evolution, function, tumor marker and more. First, though the study of conservative property and evolution pattern,we found the cluster to be highly conserved and present in most mammals. In primates, seed sequence and miRNA structure are conserved, but inter-precursor sequences are evolving. Insertions of new mi RNAs, deletions of individual mi RNAs, and a cluster duplication observed in different species suggest an actively evolving cluster. Core transcriptional machinery consisting of NANOG and OCT-4 transcription factors that define stem cells are present upstream of the mi R-302/367 cluster. Interestingly, we found the miR-302/367 cluster flanking region to be enriched as a target site of other miRNAs suggesting a mechanism for feedback control. Secondly, analysis of mi R-302 and miR-367 targets demonstrated concordance of gene set enrichment groups at high gene ontology levels, and the target genes enriched in the tumor development related pathways. Finally, we did differential expression analysis to mi R-302/367 cluster in 33 cancer types and explored its potential as tumor biomarker..When studying the expression of miR-302 family members in three different kidney tumor datasets, we observed its significant diffential expression between normal tissue and their adjacent tumor tissue, which infer miR-302 has the.capability as tumor markers.2)Since the deep sequencing proceeds, isomiRs and arm switching are consistently observed in a variety of cell types, tissues, and different cell development stages. miRNA isoforms as the products of miRBase annotated miRNA genes, are variants which are different from mature miRNAs in length and position. Arm switching is describing the phenomenon that the two mature miRNAs on the different arms of the precursor miRNA in different species, organization, or development biological systems uneven to choose to express. In this study, we mainly explore the tumor marker potential of somiRs and arm switching. We have analysised the effect of 3’ isomiR, 5’ isomiR and other type isomiR to their target genes by applying Silhouette Index supervised affinity propagation clustering, besides, we also explore their effect to cancer development and other important biology process.. thus, we apply four different variant indexes of isomi R to do differential expression analysis based on TCGA tumor dataset, they are isomiR types counts, isomi R average length, weighted average size of nucleotide according to the canonical sequence(WAZNVC) and an information entropy based index MIH. And then we use support vector machine(SVM) method combining leave one out cross validation(LOOCV) method to select the best combination of tumor markers. Finally this research studied on comparsion in three layers for arm awitching: tumor tissues and paracancer tissues, tumor tissues in different stages and tumor tissue from different organs. Results showed a significant difference in ovarian cancer in arm awitching of pre-miRNA comparied with other cancers. Specificity of arm switching between tumor tissues and paracancer tissues, and different tumors could serve as a good tumor biomarker. |
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