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      Statecharts for Gene Network Modeling

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      PLoS ONE
      Public Library of Science

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          Abstract

          State diagrams (stategraphs) are suitable for describing the behavior of dynamic systems. However, when they are used to model large and complex systems, determining the states and transitions among them can be overwhelming, due to their flat, unstratified structure. In this article, we present the use of statecharts as a novel way of modeling complex gene networks. Statecharts extend conventional state diagrams with features such as nested hierarchy, recursion, and concurrency. These features are commonly utilized in engineering for designing complex systems and can enable us to model complex gene networks in an efficient and systematic way. We modeled five key gene network motifs, simple regulation, autoregulation, feed-forward loop, single-input module, and dense overlapping regulon, using statecharts. Specifically, utilizing nested hierarchy and recursion, we were able to model a complex interlocked feed-forward loop network in a highly structured way, demonstrating the potential of our approach for modeling large and complex gene networks.

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          Most cited references36

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          Nature, nurture, or chance: stochastic gene expression and its consequences.

          Gene expression is a fundamentally stochastic process, with randomness in transcription and translation leading to cell-to-cell variations in mRNA and protein levels. This variation appears in organisms ranging from microbes to metazoans, and its characteristics depend both on the biophysical parameters governing gene expression and on gene network structure. Stochastic gene expression has important consequences for cellular function, being beneficial in some contexts and harmful in others. These situations include the stress response, metabolism, development, the cell cycle, circadian rhythms, and aging.
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            Quantitative monitoring of gene expression patterns with a complementary DNA microarray.

            A high-capacity system was developed to monitor the expression of many genes in parallel. Microarrays prepared by high-speed robotic printing of complementary DNAs on glass were used for quantitative expression measurements of the corresponding genes. Because of the small format and high density of the arrays, hybridization volumes of 2 microliters could be used that enabled detection of rare transcripts in probe mixtures derived from 2 micrograms of total cellular messenger RNA. Differential expression measurements of 45 Arabidopsis genes were made by means of simultaneous, two-color fluorescence hybridization.
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              Structure and function of the feed-forward loop network motif.

              Engineered systems are often built of recurring circuit modules that carry out key functions. Transcription networks that regulate the responses of living cells were recently found to obey similar principles: they contain several biochemical wiring patterns, termed network motifs, which recur throughout the network. One of these motifs is the feed-forward loop (FFL). The FFL, a three-gene pattern, is composed of two input transcription factors, one of which regulates the other, both jointly regulating a target gene. The FFL has eight possible structural types, because each of the three interactions in the FFL can be activating or repressing. Here, we theoretically analyze the functions of these eight structural types. We find that four of the FFL types, termed incoherent FFLs, act as sign-sensitive accelerators: they speed up the response time of the target gene expression following stimulus steps in one direction (e.g., off to on) but not in the other direction (on to off). The other four types, coherent FFLs, act as sign-sensitive delays. We find that some FFL types appear in transcription network databases much more frequently than others. In some cases, the rare FFL types have reduced functionality (responding to only one of their two input stimuli), which may partially explain why they are selected against. Additional features, such as pulse generation and cooperativity, are discussed. This study defines the function of one of the most significant recurring circuit elements in transcription networks.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2010
                23 February 2010
                : 5
                : 2
                : e9376
                Affiliations
                [1]Department of Electrical Engineering, University of Texas at Dallas, Richardson, Texas, United States of America
                Center for Genomic Regulation, Spain
                Author notes

                Conceived and designed the experiments: YJS. Performed the experiments: YJS. Analyzed the data: YJS. Contributed reagents/materials/analysis tools: YJS. Wrote the paper: YJS MN. Conceived and designed the modeling method: Y-JS. Analyzed examples: Y-JS. Contributed to verifying the logical correctness of the modeling approach: MN. Contributed to revising the paper: MN.

                Article
                09-PONE-RA-13274R1
                10.1371/journal.pone.0009376
                2826420
                20186343
                d4110363-6db2-47b6-8b45-5793be280b89
                Shin, Nourani. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                History
                : 30 September 2009
                : 1 February 2010
                Page count
                Pages: 9
                Categories
                Research Article
                Computational Biology
                Computational Biology/Genomics
                Computational Biology/Systems Biology
                Computational Biology/Transcriptional Regulation

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