Abstract
Gene regulatory networks present a wide variety of dynamical responses to intrinsic and extrinsic perturbations. Arguably, one of the most important of such coordinated responses is the one of amplification cascades, in which activation of a few key-responsive transcription factors (termed master regulators, MRs) lead to a large series of transcriptional activation events. This is so since master regulators are transcription factors controlling the expression of other transcription factor molecules and so on. MRs hold a central position related to transcriptional dynamics and control of gene regulatory networks and are often involved in complex feedback and feedforward loops inducing non-trivial dynamics. Recent studies have pointed out to the myocyte enhancing factor 2C (MEF2C, also known as MADS box transcription enhancer factor 2, polypeptide C) as being one of such master regulators involved in the pathogenesis of primary breast cancer. In this work, we perform an integrative genomic analysis of the transcriptional regulation activity of MEF2C and its target genes to evaluate to what extent are these molecules inducing collective responses leading to gene expression deregulation and carcinogenesis. We also analyzed a number of induced dynamic responses, in particular those associated with transcriptional bursts, and nonlinear cascading to evaluate the influence they may have in malignant phenotypes and cancer.Received: 20 Novembre 2014, Accepted: 24 June 2015; Edited by: C. A. Condat, G. J. Sibona; DOI: http://dx.doi.org/10.4279/PIP.070011Cite as: E Hernández-Lemus, K Baca-López, R Lemus, R García-Herrera, Papers in Physics 7, 070011 (2015)This paper, by E Hernández-Lemus, K Baca-López, R Lemus, R García-Herrera, is licensed under the Creative Commons Attribution License 3.0.
Highlights
Transcriptional master regulatorsPhenotypic conditions in living cells are largely determined by the interplay of a multitude of molecules; in particular, genes and their protein products
Aside from this, a non-equilibrium thermodynamics analysis of the coupling between transcriptional regulation processes and metabolic de-regulation in breast cancer cells has led to some further evidence pointing out to MEF2C as an master regulators (MRs) that may be playing an important role in carcinogenic processes
The results of the transcription factor binding sites (TFBS) analysis showed that the set of MEF2C targets includes a number of genes that participate in oncogenic processes such as MRAS, IGFBP3, CTNND1, FOXN3, FOXP4, Figure 3: Gene regulatory network including up to second order transcriptional interactions in MEF2C targets
Summary
Phenotypic conditions in living cells are largely determined by the interplay of a multitude of molecules; in particular, genes and their protein products. Context-dependent analysis of regulatory activity of particular cellular phenotypes (say tumor cells) may be performed with the aid of transcriptional interaction networks Such GRNs present a complex topology, often compliant with a scale-free hierarchic nature, in which a relatively small number of key players dominate the function and dynamics of the network. MRs are transcription factor genes that are located upstream in the genomic regulation programme, they possess a high hierarchy in the GRN They are considered to be important players behind the presence of (some) amplification cascades in transcriptional regulatory networks, and it has been hypothesized that they may coordinate the dynamic transcriptional response and phenotype (in the case of eukaryotes) of the cells. Such a gene may be acting as a transcriptional master regulator over that specific cell condition (phenotype)
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