Correlation-Based Network Generation, Visualization, and Analysis as a Powerful Tool in Biological Studies: A Case Study in Cancer Cell Metabolism

Batushansky, Albert; Toubiana, David; Fait, Aaron

doi:10.1155/2016/8313272

Cited by 80 publications

(68 citation statements)

References 38 publications

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“…As a second approach for identifying the functionally most relevant miRNAs among the 23 found to be differentially expressed by microarray, we built an expression network for these miRNAs (37). This represents a high-level correlation between the miRNA expression in a given group of patients and is composed of nodes (the miRNAs) and of edges (high correlations between the expression of 2 miRNAs) (38,39). The miRNA network of nonresponders is far more connected compared with responders ( Figure 1C): it contains 104 edges, being a well-connected network with 14 nodes with over 10 edges each (nodes with high node connectivity, 0.4783-0.6087).…”

Section: Resultsmentioning

confidence: 99%

miR-543 regulates the epigenetic landscape of myelofibrosis by targeting TET1 and TET2

Fuentes‐Mattei¹,

Bayraktar²,

Manshouri³

et al. 2020

JCI Insight

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Myelofibrosis (MF) is a myeloproliferative neoplasm characterized by cytopenia and extramedullary hematopoiesis, resulting in splenomegaly. Multiple pathological mechanisms (e.g., circulating cytokines and genetic alterations, such as JAK V617F mutation) have been implicated in the etiology of MF, but the molecular mechanism causing resistance to JAK2 V617F inhibitor therapy remains unknown. Among MF patients who were treated with the JAK inhibitor ruxolitinib, we compared noncoding RNA profiles of ruxolitinib therapy responders versus nonresponders and found miR-543 was significantly upregulated in nonresponders. We validated these findings by reverse transcription-quantitative PCR. in this same cohort, in 2 additional independent MF patient cohorts from the United States and Romania, and in a JAK2 V617F mouse model of MF. Both in vitro and in vivo models were used to determine the underlying molecular mechanism of miR-543 in MF. Here, we demonstrate that miR-543 targets the dioxygenases ten-eleven translocation 1 (TET1) and 2 (TET2) in patients and in vitro, causing increased levels of global 5-methylcytosine, while decreasing the acetylation of histone 3, STAT3, and tumor protein p53. Mechanistically, we found that activation of STAT3 by JAKs epigenetically controls miR-543 expression via binding the promoter region of miR-543. Furthermore, miR-543 upregulation promotes the expression of genes related to drug metabolism, including CYP3A4, which is involved in ruxolitinib metabolism. Our findings suggest miR-543 as a potentially novel biomarker for the prognosis of MF patients with a high risk of treatment resistance and as a potentially new target for the development of new treatment options.

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Section: Resultsmentioning

confidence: 99%

miR-543 regulates the epigenetic landscape of myelofibrosis by targeting TET1 and TET2

Fuentes‐Mattei¹,

Bayraktar²,

Manshouri³

et al. 2020

JCI Insight

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“…The P value that reflects significance of correlation did not strongly affect network density and was selected on a level equal to 0.001. The significant correlation matrix was created using the freely distributed R software (version 3.0.1; www.r-project.org), and the network visualization and analysis was applied using Cytoscape, version 3.0 (Shannon et al, 2003), using a previously described method (Batushansky et al, 2016). Each node represents a specific amino acid; the node properties (color and size) reflect attributes of biochemical pathways and nodal degree, respectively.…”

Section: Network Analysismentioning

confidence: 99%

Network-Guided GWAS Improves Identification of Genes Affecting Free Amino Acids

et al. 2016

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Amino acids are essential for proper growth and development in plants. Amino acids serve as building blocks for proteins but also are important for responses to stress and the biosynthesis of numerous essential compounds. In seed, the pool of free amino acids (FAAs) also contributes to alternative energy, desiccation, and seed vigor; thus, manipulating FAA levels can significantly impact a seed's nutritional qualities. While genome-wide association studies (GWAS) on branched-chain amino acids have identified some regulatory genes controlling seed FAAs, the genetic regulation of FAA levels, composition, and homeostasis in seeds remains mostly unresolved. Hence, we performed GWAS on 18 FAAs from a 313-ecotype Arabidopsis (Arabidopsis thaliana) association panel. Specifically, GWAS was performed on 98 traits derived from known amino acid metabolic pathways (approach 1) and then on 92 traits generated from an unbiased correlation-based metabolic network analysis (approach 2), and the results were compared. The latter approach facilitated the discovery of additional novel metabolic interactions and singlenucleotide polymorphism-trait associations not identified by the former approach. The most prominent network-guided GWAS signal was for a histidine (His)-related trait in a region containing two genes: a cationic amino acid transporter (CAT4) and a polynucleotide phosphorylase resistant to inhibition with fosmidomycin. A reverse genetics approach confirmed CAT4 to be responsible for the natural variation of His-related traits across the association panel. Given that His is a semiessential amino acid and a potent metal chelator, CAT4 orthologs could be considered as candidate genes for seed quality biofortification in crop plants.Free amino acids (FAAs) play a pivotal role in the central metabolism of plants. FAAs serve as building blocks for protein synthesis and also are precursors for osmolytes, alternative energy, hormones, and key secondary metabolites (Rai, 2002; Araújo et al., 2010;Tzin and Galili, 2010; Angelovici et al., 2011). Studies of both developing and germinating seeds also have implicated FAAs in proper seed development and germination (Angelovici et al., 2010;Galili and Amir, 2013). Still, the genetic control of FAA metabolism in seed remains poorly understood. One reason is that FAA metabolism is tightly intertwined with essential cellular processes in plants, and manipulating FAA levels can have strong deleterious, pleiotropic effects on the entire system (Guyer et al., 1995;Galili, 2011;Ingle, 2011;Pratelli and Pilot, 2014). For example, increasing Lys and Thr inhibits the activity of Asp kinase via a feedback inhibition loop (Clark and Lu, 2015). At high concentrations, this inhibition can lead to starvation of a downstream metabolic product, Met, which inhibits plant growth (Bright et al., 1982;Rognes et al., 1983;Heremans and Jacobs, 1995). In addition, several amino acid catabolic products, such as those emanating from branched-chain amino acids (BCAAs) or Lys degradation pathways, can be chan...

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“…The task of the correlation analysis method is to determine correlations between the studied parameters, the nature and pronouncement of which are established by the pair correlation coefficient (Akoglu, 2018;Schober et al, 2018;Uurtio et al, 2018). Prolonged use of the method facilitated the data accumulation for studying various biomedical processes (Miot, 2017(Miot, , 2018Yadav, 2018) at their multiple levels (Rossi et al, 2015;Maranzatto et al, 2016;Kim et al, 2017), which resulted in the development of tools to facilitate visualization, analysis and interpretation of the information obtained (Mutwil et al, 2010;Batushansky et al, 2016). However, the method is not intended to work with qualitative or binary data on the state of a studied biosystem.…”

Section: Introductionmentioning

confidence: 99%

Application of correlation analysis in cytology: Opportunities to study specific activity of follicular thyrocytes

Ryabukha

Dronyuk

2019

Regul. Mech. Biosyst.

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The task of biomedical diagnostics is to determine the dependence of the conclusion/diagnosis on the sets of parameters that characterize the state of the biosystem/patient. The performed analytical review of modern scientific literature permitted us to determine that Bayesian, regression and correlation analyzes and logical programming are most often used for biomedical diagnostics purposes. At the same time, their informativeness can only be realized for the solution of those diagnostic tasks in which quantitative parameters are analyzed. Qualitative and binary information provides an opportunity to find out more about features of the biosystem’s state. However, its use is limited, since the results obtained are presented in words (that is, in a linguistic form) that cannot be processed by means of traditional (digital) mathematical analysis. The objective of this work was determining the capabilities of the mathematical apparatus to deepen the study of hormonopoiesis in the thyroid gland. The object of the study was electron micrographs of ultrathin tissue sections, its subject was the features of correlations between ultrastructural cell elements which carry out the processes of synthesis and secretion in follicular thyrocytes. In the context of studying the features of synthetic and secretory activity of follicular thyrocytes of the thyroid glands in white male rats, it was shown that the objectification of non-numerical information about the state of cells allows us to use linguistic information about changes in their morphofunctional state. Implementation of correlation analysis for studying the relationships and interdependencies between organelles which implement synthesis and secretion of the hormonal product in the main structural unit of the thyroid gland – follicular thyrocyte – allows us to determine, study, analyze and generalize peculiarities of both changes in individual ultrastructures and their functional complexes (clusters) in response to the actions of various factors and to trace the interdependencies and mutual interactions existing between them, as well as to deepen the idea of the intimate mechanism features of the specific directions of follicular thyrocyte activity, which substantially expands the research platform in cytophysiology and cytomorphology.

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Correlation-Based Network Generation, Visualization, and Analysis as a Powerful Tool in Biological Studies: A Case Study in Cancer Cell Metabolism

Cited by 80 publications

References 38 publications

miR-543 regulates the epigenetic landscape of myelofibrosis by targeting TET1 and TET2

miR-543 regulates the epigenetic landscape of myelofibrosis by targeting TET1 and TET2

Network-Guided GWAS Improves Identification of Genes Affecting Free Amino Acids

Application of correlation analysis in cytology: Opportunities to study specific activity of follicular thyrocytes

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