Integrated analysis of mutations, miRNA and mRNA expression in glioblastoma

BACKGROUND: Glioblastoma arises from complex interactions between a variety of genetic alterations and environmental perturbations. Little attention has been paid to understanding how genetic variations, altered gene expression and microRNA (miRNA) expression are integrated into networks which act together to alter regulation and finally lead to the emergence of complex phenotypes and glioblastoma. RESULTS: We identified association of somatic mutations in 14 genes with glioblastoma, of which 8 genes are newly identified, and association of loss of heterozygosity (LOH) is identified in 11 genes with glioblastoma, of which 9 genes are newly discovered. By gene coexpression network analysis, we indentified 15 genes essential to the function of the network, most of which are cancer related genes. We also constructed miRNA coexpression networks and found 19 important miRNAs of which 3 were significantly related to glioblastoma patients' survival. We identified 3,953 predicted miRNA-mRNA pairs, of which 14 were previously verified by experiments in other groups. Using pathway enrichment analysis we also found that the genes in the target network of the top 19 important miRNAs were mainly involved in cancer related signaling pathways, synaptic transmission and nervous systems processes. Finally, we developed new methods to decipher the pathway connecting mutations, expression information and glioblastoma. We indentified 4 cis-expression quantitative trait locus (eQTL): TP53, EGFR, NF1 and PIK3C2G; 262 trans eQTL and 26 trans miRNA eQTL for somatic mutation; 2 cis-eQTL: NRAP and EGFR; 409 trans- eQTL and 27 trans- miRNA eQTL for lost of heterozygosity (LOH) mutation. CONCLUSIONS: Our results demonstrate that integrated analysis of multi-dimensional data has the potential to unravel the mechanism of tumor initiation and progression

A gene-based approach for testing association of rare alleles

Rare genetic variants have been shown to be important to the susceptibility of common human diseases. Methods for detecting association of rare genetic variants are drawing much attention. In this report, we applied a gene-based approach to the 200 simulated data sets of unrelated individuals. The test can detect the association of some genes with multiple rare variants

MicroRNAs and human cancer

MicroRNAs (miRNAs) are a recently discovered family of short non-coding RNA molecules of about 19–24 nucleotides in length that are involved in regulation of gene expression. These small molecules have been found to regulate genes involved in diverse biological processes such as cell proliferation, development, differentiation, apoptosis and others. MiRNAs regulate gene expression at the post-transcriptional level either by inhibition of the target (mRNA) or by its destruction. Recent studies have shown that mRNA deregulation is a basic problem in studying pathogenesis of many malignant tumors. It has been recently shown that miRNAs are able to regulate thousands of target genes simultaneously. Thus, the key role of miRNA in carcinogenesis reveals a new layer in the molecular architecture of cancer. Patterns of altered miRNA expression in cancer may serve as molecular biomarkers for tumor diagnosis, prognosis of disease-specific outcomes, and prediction of therapeutic responses. Furthermore, miRNAs may serve as specific targets of new gene therapies

Integrative Pathway Analysis Using Graph-Based Learning with Applications to TCGA Colon and Ovarian Data

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Profiling of circulating microRNAs: from single biomarkers to re-wired networks

The recent discovery that microRNAs (miRNAs) are present in the circulation sparked interest in their use as potential biomarkers. In this review, we will summarize the latest findings on circulating miRNAs and cardiovascular disease but also discuss analytical challenges. While research on circulating miRNAs is still in its infancy, high analytical standards in statistics and study design are a prerequisite to obtain robust data and avoid repeating the mistakes of the early genetic association studies. Otherwise, studies tend to get published because of their novelty despite low numbers, poorly matched cases and controls and no multivariate adjustment for conventional risk factors. Research on circulating miRNAs can only progress by bringing more statistical rigour to bear in this field and by evaluating changes of individual miRNAs in the context of the overall miRNA network. Such miRNA signatures may have better diagnostic and prognostic value

Novel principles of gamma-retroviral insertional transcription activation in murine leukemia virus-induced end-stage tumors

BACKGROUND: Insertional mutagenesis screens of retrovirus-induced mouse tumors have proven valuable in human cancer research and for understanding adverse effects of retroviral-based gene therapies. In previous studies, the assignment of mouse genes to individual retroviral integration sites has been based on close proximity and expression patterns of annotated genes at target positions in the genome. We here employed next-generation RNA sequencing to map retroviral-mouse chimeric junctions genome-wide, and to identify local patterns of transcription activation in T-lymphomas induced by the murine leukemia gamma-retrovirus SL3-3. Moreover, to determine epigenetic integration preferences underlying long-range gene activation by retroviruses, the colocalization propensity with common epigenetic enhancer markers (H3K4Me1 and H3K27Ac) of 6,117 integrations derived from end-stage tumors of more than 2,000 mice was examined. RESULTS: We detected several novel mechanisms of retroviral insertional mutagenesis: bidirectional activation of mouse transcripts on opposite sides of a provirus including transcription of unannotated mouse sequence; sense/antisense-type activation of genes located on opposite DNA strands; tandem-type activation of distal genes that are positioned adjacently on the same DNA strand; activation of genes that are not the direct integration targets; combination-type insertional mutagenesis, in which enhancer activation, alternative chimeric splicing and retroviral promoter insertion are induced by a single retrovirus. We also show that irrespective of the distance to transcription start sites, the far majority of retroviruses in end-stage tumors colocalize with H3K4Me1 and H3K27Ac-enriched regions in murine lymphoid tissues. CONCLUSIONS: We expose novel retrovirus-induced host transcription activation patterns that reach beyond a single and nearest annotated gene target. Awareness of this previously undescribed layer of complexity may prove important for elucidation of adverse effects in retroviral-based gene therapies. We also show that wild-type gamma-retroviruses are frequently positioned at enhancers, suggesting that integration into regulatory regions is specific and also subject to positive selection for sustaining long-range gene activation in end-stage tumors. Altogether, this study should prove useful for extrapolating adverse outcomes of retroviral vector therapies, and for understanding fundamental cellular regulatory principles and retroviral biology

Systems genetics identifies miRNA-mediated regulation of host response in COVID-19.

peer reviewed[en] BACKGROUND: Individuals infected with SARS-CoV-2 vary greatly in their disease severity, ranging from asymptomatic infection to severe disease. The regulation of gene expression is an important mechanism in the host immune response and can modulate the outcome of the disease. miRNAs play important roles in post-transcriptional regulation with consequences on downstream molecular and cellular host immune response processes. The nature and magnitude of miRNA perturbations associated with blood phenotypes and intensive care unit (ICU) admission in COVID-19 are poorly understood. RESULTS: We combined multi-omics profiling-genotyping, miRNA and RNA expression, measured at the time of hospital admission soon after the onset of COVID-19 symptoms-with phenotypes from electronic health records to understand how miRNA expression contributes to variation in disease severity in a diverse cohort of 259 unvaccinated patients in Abu Dhabi, United Arab Emirates. We analyzed 62 clinical variables and expression levels of 632 miRNAs measured at admission and identified 97 miRNAs associated with 8 blood phenotypes significantly associated with later ICU admission. Integrative miRNA-mRNA cross-correlation analysis identified multiple miRNA-mRNA-blood endophenotype associations and revealed the effect of miR-143-3p on neutrophil count mediated by the expression of its target gene BCL2. We report 168 significant cis-miRNA expression quantitative trait loci, 57 of which implicate miRNAs associated with either ICU admission or a blood endophenotype. CONCLUSIONS: This systems genetics study has given rise to a genomic picture of the architecture of whole blood miRNAs in unvaccinated COVID-19 patients and pinpoints post-transcriptional regulation as a potential mechanism that impacts blood traits underlying COVID-19 severity. The results also highlight the impact of host genetic regulatory control of miRNA expression in early stages of COVID-19 disease

MicroRNA regulation of glycolytic metabolism in glioblastoma multiforme

Glioblastoma multiforme (GBM) is the most aggressive and common malignant brain and central nervous system tumour. A well-known hallmark of GMB, and many other tumours, is aerobic glycolysis. microRNAs (miRNAs) are a class of short non-protein coding sequences that exert post-transcriptional controls on gene expression and represent critical regulators of aerobic glycolysis in GBM. In GBM, miRNAs regulate the expression of glycolytic genes directly and via the regulation of metabolism-associated oncogenic pathways, such as the PI3K/Akt signalling pathway. The aim of this review is to establish links between miRNA expression levels, disease grade and prognosis, and the glycolytic phenotype of GBM. In this review, the involvement of 25 miRNAs in the regulation of glycolytic metabolism of GBM is discussed. Seven of these miRNAs have been shown to regulate glycolytic metabolism in other tumour types. Further eight miRNAs, which have been shown to be differentially expressed in GBM, were also reported to play a regulatory role in glycolysis in other cancer types. Such miRNAs could serve as potential glycolytic regulators in GBM but require functional validation. This review concludes with presenting a number of glycolytic regulatory miRNAs that have demonstrated their therapeutic potential either alone or as adjuvants in GBM, despite the major challenges that have to be solved before miRNA-based therapies can widely be used for the treatment of GBM patients