Enhancing identification of cancer types via lowly-expressed microRNAs.
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ABSTRACT:
SUBMITTER: Rasnic R
PROVIDER: S-EPMC5435932 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:To study the evolution of human microRNAs (miRNAs), we examined nucleotide variation in humans, sequence divergence between species, and genomic clustering patterns for miRNAs with different expression levels. We found that expression level is a major indicator of the rate of evolution and that approximately 30% of currently annotated human miRNA genes are almost free of selective pressure.
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Project description:microRNAs (miRNAs) functioning in gene silencing have been associated with cancer progression. However, common abnormal miRNA expression patterns and their potential roles in cancer have not yet been evaluated. To account for individual differences between patients, we retrieved miRNA sequencing data for 575 patients with both tumor and adjacent non-tumorous tissues from 14 cancer types from The Cancer Genome Atlas (TCGA). We then performed differential expression analysis using DESeq2 and edgeR. Results showed that cancer types can be grouped based on the distribution of miRNAs with different expression patterns between tumor and non-tumor samples. We found 81 significantly differentially expressed miRNAs (SDEmiRNAs) in a single cancer. We also found 21 key SDEmiRNAs (nine over-expressed and 12 under-expressed) associated with at least eight cancers each and enriched in more than 60% of patients per cancer, including four newly identified SDEmiRNAs (hsa-mir-4746, hsa-mir-3648, hsa-mir-3687, and hsa-mir-1269a). The downstream effects of these 21 SDEmiRNAs on cellular function were evaluated through enrichment and pathway analysis of 7186 protein-coding gene targets mined from literature reports of differential expression of miRNAs in cancer. This analysis enables identification of SDEmiRNA functional similarity in cell proliferation control across a wide range of cancers, and assembly of common regulatory networks over cancer-related pathways. These findings were validated by construction of a regulatory network in the PI3K pathway. This study provides evidence for the value of further analysis of SDEmiRNAs as potential biomarkers and therapeutic targets for cancer diagnosis and treatment.
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Project description:Engineering clinically relevant cells in vitro holds promise for regenerative medicine, but most protocols fail to faithfully recapitulate target cell properties. To address this, we developed CellNet, a network biology platform that determines whether engineered cells are equivalent to their target tissues, diagnoses aberrant gene regulatory networks, and prioritizes candidate transcriptional regulators to enhance engineered conversions. Using CellNet, we improved B cell to macrophage conversion, transcriptionally and functionally, by knocking down predicted B cell regulators. Analyzing conversion of fibroblasts to induced hepatocytes (iHeps), CellNet revealed an unexpected intestinal program regulated by the master regulator Cdx2. We observed functional engraftment of mouse colon by iHeps, thereby establishing their broader potential as endoderm progenitors and demonstrating direct conversion of fibroblasts into intestinal epithelium. Our studies illustrate how CellNet can be employed to improve direct conversion and to uncover unappreciated properties of engineered cells. 15 samples
2014-08-14 | E-GEOD-59037 | biostudies-arrayexpress
Project description:Codon usage bias affects the genomes of organisms from all kingdoms of life and results from both background substitution biases and natural selection. Natural selection on codon usage to increase translation accuracy and efficiency has long been known to affect gene sequences. Such selection is stronger on highly, compared with lowly expressed genes, resulting in higher levels of codon bias within genes with higher expression levels. Additionally, selection on translation accuracy affects more strongly codons encoding conserved amino acids, since these will more often affect protein folding and/or function. By applying tests of selection on the gene sequences of the bacterium Escherichia coli, we demonstrate that both highly and lowly expressed genes display signals of selection on codon usage. Such signals are found for both conserved and less conserved amino acid positions, even within the 10% of E. coli genes expressed at the lowest levels. We further demonstrate experimentally that single synonymous codon replacements within a lowly expressed, essential gene can carry substantial effects on bacterial fitness. Combined, our results demonstrate that even within genes expressed at relatively low levels there is substantial selection on codon usage and that single synonymous codon replacements within such genes can have a marked effect on bacterial fitness.
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Project description:BackgroundMicroRNAs (miRNAs) are small noncoding RNAs (~22 nucleotides) that regulate gene expression by cleaving mRNAs or inhibiting translation. The baboon is a well-characterized cardiovascular disease model; however, no baboon miRNAs have been identified. Evidence indicates that the baboon and human genomes are highly conserved; based on this conservation, we hypothesized that comparative genomic methods could be used to identify baboon miRNAs.MethodsWe employed an in silico comparative genomics approach and human miRNA arrays to identify baboon expressed miRNAs in liver (n = 6) and lymphocytes (n = 6). Expression profiles for selected miRNAs in multiple tissues were validated by RT-PCR.ResultsWe identified in silico 555 putative baboon pre-miRNAs, of which 41% exhibited 100% identity and an additional 58% shared more than 90% sequence identity with human pre-miRNAs. Some of these miRNAs are primate-specific and are clustered in the baboon genome like human miRNA clusters. We detected expression of 494 miRNAs on the microarray and validated expression of selected miRNAs in baboon liver and lymphocytes by RT-PCR. We also observed miRNA expression in additional tissues relevant to dyslipidemia and atherosclerosis. Approximately half of the miRNAs expressed on the array were not predicted in silico suggesting that we have identified novel baboon miRNAs, which could not be predicted using the current draft of the baboon genome.ConclusionWe identified a subset of baboon miRNAs using a comparative genomic approach, identified additional baboon miRNAs using a human array and showed tissue-specific expression of baboon miRNAs. Our discovery of baboon miRNAs in liver and lymphocytes will provide resources for studies on the roles of miRNAs in dyslipidemia and atherosclerosis, and for translational studies.
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Project description:The spatiotemporal program of metazoan DNA replication is regulated during development and altered in cancers. We have generated novel OK-seq, Repli-seq and RNA-seq data to compare the DNA replication and gene expression programs of twelve cancer and non-cancer human cell types. Changes in replication fork directionality (RFD) determined by OK-seq are widespread but more frequent within GC-poor isochores and largely disconnected from transcription changes. Cancer cell RFD profiles cluster with non-cancer cells of similar developmental origin but not with different cancer types. Importantly, recurrent RFD changes are detected in specific tumour progression pathways. Using a model for establishment and early progression of chronic myeloid leukemia (CML), we identify 1027 replication initiation zones (IZs) that progressively change efficiency during long-term expression of the BCR-ABL1 oncogene, being twice more often downregulated than upregulated. Prolonged expression of BCR-ABL1 results in targeting of new IZs and accentuation of previous efficiency changes. Targeted IZs are predominantly located in GC-poor, late replicating gene deserts and frequently silenced in late CML. Prolonged expression of BCR-ABL1 results in massive deletion of GC-poor, late replicating DNA sequences enriched in origin silencing events. We conclude that BCR-ABL1 expression progressively affects replication and stability of GC-poor, late-replicating regions during CML progression.
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Project description:Tumor metastasis continues to be the most significant contributor to cancer related mortality, and although several studies have examined expression profiles emanating from patients with metastatic disease, very little information is available about signatures that differentiate metastatic lesions from primary tumors and associated normal tissues, largely because such matched tissue sample series are rare. This study was specifically designed to identify the metastasis relevant microRNAs in colorectal cancer and characterize microRNAs that modulate the metastatic phenotype. Here we describe in detail how the data, deposited in the Gene Expression Omnibus (GEO) with the accession number GSE54088, was generated including the basic analysis as contained in the manuscript published in Cancer Research with the PMID 26069251.
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Project description:Background:Ovarian cancer (OC) is a common gynecological cancer and characterized by high metastatic potential. MicroRNAs (miRNAs, miRs) have the promise to be harnessed as prognostic and therapeutic biomarkers for OC. Herein, we sought to identify differentially expressed miRNAs and mRNAs in metastatic OC, and to validate them with functional experiments. Methods:Differentially expressed miRNAs and mRNAs were screened from six pairs of primary OC tissues and metastatic tissues using a miRStar™ Human Cancer Focus miRNA and Target mRNA PCR Array. Then, gene expression profiling results were verified by reverse transcription quantitative polymerase chain reaction (RT-qPCR) and western blot assays. The binding affinity between miR-7-5p and TGF?2 was validated by dual-luciferase reporter assay. Expression of miR-7-5p and TGF?2 was manipulated to assess their roles in malignant phenotypes of highly metastatic HO-8910PM cells. Results:MiRNA profiling and sequencing identified 12 miRNAs and 10 mRNAs that were differentially expressed in metastatic tissues. Gene ontology and Pathway analyses determined that 3 differentially expressed mRNAs (ITGB3, TGF?2 and TNC) were related to OC metastasis. The results of RT-qPCR confirmed that the decrease of miR-7-5p was most significant in OC metastasis, while TGF?2 was up-regulated in OC metastasis. Moreover, miR-7-5p targeted and negatively regulated TGF?2. MiR-7-5p overexpression accelerated HO-8910PM cell viability and invasion, and TGF?2 overexpression reversed the results. Meanwhile, simultaneous miR-7-5p and TGF?2 overexpression rescued the cell activities. Conclusions:This study characterizes differentially expressed miRNAs and mRNAs in metastatic OC, where miR-7-5p and its downstream target were most closely associated with metastatic OC. Overexpression of miR-7-5p targets and inhibits TGF?2 expression, thereby inhibiting the growth and metastasis of OC.
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Project description:Engineering clinically relevant cells in vitro holds promise for regenerative medicine, but most protocols fail to faithfully recapitulate target cell properties. To address this, we developed CellNet, a network biology platform that determines whether engineered cells are equivalent to their target tissues, diagnoses aberrant gene regulatory networks, and prioritizes candidate transcriptional regulators to enhance engineered conversions. Using CellNet, we improved B cell to macrophage conversion, transcriptionally and functionally, by knocking down predicted B cell regulators. Analyzing conversion of fibroblasts to induced hepatocytes (iHeps), CellNet revealed an unexpected intestinal program regulated by the master regulator Cdx2. We observed long-term functional engraftment of mouse colon by iHeps, thereby establishing their broader potential as endoderm progenitors and demonstrating direct conversion of fibroblasts into intestinal epithelium. Our studies illustrate how CellNet can be employed to improve direct conversion and to uncover unappreciated properties of engineered cells.
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Project description:We present a spatio-temporal assessment of microRNA (miRNA) expression throughout early human brain development. We assessed the prefrontal cortex, hippocampus and cerebellum of 18 normal human donor brains spanning infancy through adolescence by RNA-seq. We discovered differentially expressed miRNAs and broad miRNA patterns across both temporal and spatial dimensions, and between male and female prefrontal cortex. Putative target genes of the differentially expressed miRNAs were identified, which demonstrated functional enrichment for transcription regulation, synaptogenesis and other basic intracellular processes. Sex-biased miRNAs also targeted genes related to Wnt and transforming growth factor-beta pathways. The differentially expressed miRNA targets were highly enriched for gene sets related to autism, schizophrenia, bipolar disorder and depression, but not neurodegenerative diseases, epilepsy or other adult-onset psychiatric diseases. Our results suggest critical roles for the identified miRNAs in transcriptional networks of the developing human brain and neurodevelopmental disorders.
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