担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）

Living organisms must respond to environmental changes. Generally, accurate and rapid responses are provided by simple, unidirectional networks that connect inputs with outputs. Besides accuracy and speed, however, biological responses should also be robust to environmental or intracellular noise and mutations. Furthermore, cells must also respond to unforeseen environmental changes that have not previously been experienced, to avoid extinction prior to the evolutionary rewiring of their networks, which takes numerous generations. To address the question of how cells can make robust adaptation even to unforeseen challenges, we have investigated gene regulatory networks that mutually activate or inhibit, and we have demonstrated that complex entangled networks can make appropriate input-output relationships that satisfy such adaptive responses. Such entangled networks function when the expression of each gene shows sloppy and unreliable responses with low Hill coefficient reactions. To compensate for such sloppiness, several detours in the regulatory network exist. By taking advantage of the averaging over such detours, the network shows a higher robustness to environmental and intracellular noise as well as to mutations in the network, when compared to simple unidirectional circuits. Furthermore, it is demonstrated that the appropriate response to unforeseen environmental changes, allowing for functional outputs, is achieved as many genes exhibit similar dynamic expression responses, irrespective of inputs including unforeseen inputs. The similarity of the responses is statistically confirmed by applying dynamic time warping and dynamic mode decomposition methods. As complex entangled networks are commonly observed in the data in gene regulatory networks whereas global gene expression responses are measured in transcriptome analysis in microbial experiments, the present results give an answer to how cells make adaptive responses and also provide a different design principle for cellular networks.

DOI： 10.1103/PhysRevResearch.3.033183

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）

Gene expression dynamics satisfying given input-output relationships were investigated by evolving the networks for an optimal response. We found three types of networks and corresponding dynamics, depending on the sensitivity of the gene expression dynamics: direct response with straight paths, amplified response by a feed-forward network, and cooperative response with a complex network. When the sensitivity of each gene's response is low and expression dynamics is sloppy, the last type is selected, in which many genes respond collectively to inputs, with local-excitation and global-inhibition structures. Robustness to noise is also demonstrated. The result provides an insight into how a reliable response is achieved with unreliable units, and on why complex networks are adopted in cells.

DOI： 10.1209/0295-5075/124/38002

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）

Regulation of gene expression levels is essential for all living systems and transcription factors (TFs) are the main regulators of gene expression through their ability to repress or induce transcription. A balance between synthesis and degradation rates controls gene expression levels. To determine which rate is dominant, we analyzed the correlation between expression levels of a TF and its regulated gene based on a mathematical model. We selected about 280,000 expression patterns of 355 TFs and 647 regulated genes using DNA microarray data from the Gene Expression Omnibus (GEO) data repository. Based on our model, correlation between the expressions of TF±regulated gene pairs corresponds to tuning of the synthesis rate, whereas no correlation indicates excessive synthesis and requires tuning of the degradation rate. The gene expression relationships between TF± regulated gene pairs were classified into four types that correspond to different gene regulatory mechanisms. It was surprising that fewer than 20% of these genes were governed by the familiar regulatory mechanism, i.e., through the synthesis rate. Moreover, we performed pathway analysis and found that each classification type corresponded to distinct gene functions: cellular regulation pathways were dominant in the type with synthesis rate regulation and terms associated with diseases such as cancer, Parkinson's disease, and Alzheimer's disease were dominant in the type with degradation rate regulation. Interestingly, these diseases are caused by the accumulation of proteins. These results indicated that gene expression is regulated structurally, not arbitrarily, according to the gene function. This funding is indicative of a systematic control of transcription processes at the whole-cell level.

DOI： 10.1371/journal.pone.0177430

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受賞国：日本国