Repeated Small Perturbation Approach Reveals Transcriptomic Steady States

PLOS ONE, Dec 2019

The study of biological systems dynamics requires elucidation of the transitions of steady states. A “small perturbation” approach can provide important information on the “steady state” of a biological system. In our experiments, small perturbations were generated by applying a series of repeating small doses of ultraviolet radiation to a human keratinocyte cell line, HaCaT. The biological response was assessed by monitoring the gene expression profiles using cDNA microarrays. Repeated small doses (10 J/m2) of ultraviolet B (UVB) exposure modulated the expression profiles of two groups of genes in opposite directions. The genes that were up-regulated have functions mainly associated with anti-proliferation/anti-mitogenesis/apoptosis, and the genes that were down-regulated were mainly related to proliferation/mitogenesis/anti-apoptosis. For both groups of genes, repetition of the small doses of UVB caused an immediate response followed by relaxation between successive small perturbations. This cyclic pattern was suppressed when large doses (233 or 582.5 J/m2) of UVB were applied. Our method and results contribute to a foundation for computational systems biology, which implicitly uses the concept of steady state.

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Repeated Small Perturbation Approach Reveals Transcriptomic Steady States

et al. (2011) Repeated Small Perturbation Approach Reveals Transcriptomic Steady States. PLoS ONE 6(12): e29241. doi:10.1371/journal.pone.0029241 Repeated Small Perturbation Approach Reveals Transcriptomic Steady States Ching-Lung Huang 0 Wun-Yi Shu 0 Min-Lung Tsai 0 Chi-Shiun Chiang 0 Cheng-Wei Chang 0 Chiu-Ting Chang 0 Ian C. Hsu 0 Raya Khanin, Memorial Sloan Kettering Cancer Center, United States of America 0 1 Department of Biomedical Engineering and Environmental Sciences, National Tsing Hua University , Hsinchu, Taiwan , 2 Institute of Statistics, National Tsing Hua University , Hsinchu, Taiwan , 3 Institute of Athletics, National Taiwan Sport University , Taichung , Taiwan The study of biological systems dynamics requires elucidation of the transitions of steady states. A ''small perturbation'' approach can provide important information on the ''steady state'' of a biological system. In our experiments, small perturbations were generated by applying a series of repeating small doses of ultraviolet radiation to a human keratinocyte cell line, HaCaT. The biological response was assessed by monitoring the gene expression profiles using cDNA microarrays. Repeated small doses (10 J/m2) of ultraviolet B (UVB) exposure modulated the expression profiles of two groups of genes in opposite directions. The genes that were up-regulated have functions mainly associated with anti-proliferation/antimitogenesis/apoptosis, and the genes that were down-regulated were mainly related to proliferation/mitogenesis/antiapoptosis. For both groups of genes, repetition of the small doses of UVB caused an immediate response followed by relaxation between successive small perturbations. This cyclic pattern was suppressed when large doses (233 or 582.5 J/m2) of UVB were applied. Our method and results contribute to a foundation for computational systems biology, which implicitly uses the concept of steady state. - Funding: NSC 99-2112-M-007-008, NSC, Taiwan. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. . These authors contributed equally to this work. Systems biology studies the dynamics of networks of interacting molecules in living organisms [1,2]. According to the new paradigm for biomedical study proposed by Kitano [2], a systems framework for biology has at least four key properties: I) system structure, II) system dynamics, III) control method, and IV) design method. An adequate experimental method of studying biological systems dynamics, particularly the transitions of physiological states (defined [3,4,5] according to various factors such as amounts of metabolites corresponding to metabolic states or RNA expression profiles for transcriptional states), has not yet been developed. Beyond the physiological state, physiological robustness [2] is also an essential feature for life to be maintained. To maintain the physiological robustness, a variety of levels of robustness, including transcriptomic expression, are critical. This can be referred as the transcriptomic expression steady state. To unravel the complex regulatory networks underlying a living organism, many systems approaches have been applied to biological model systems. In those studies, chemical treatment [6], radiation exposure [7,8], and physical stresses [9,10] were frequently used to investigate their corresponding biological effects. However, the stimuli commonly used to investigate state transitions are often so intense that they casue exaggerated results leading to irreversible transitions of biological states, thus obscuring the physiological responses that occur under normal conditions. Here we present a new method of studying systems dynamics using a small perturbation technique; we also experimentally demonstrated the existence of steady states at the transcription level. The concepts of small perturbation and steady state used here are adapted from quantum physics. We used small doses of UVB radiation as a source of small perturbations to explore the gene expression profiles of disturbed biological states in auto-transformed human keratinocytes (HaCaT) [11]. Following repeated small perturbations of 10 J/m2 UVB, two opposite classes of genes, one down-regulated and the other upregulated, exhibited an immediate response followed by relaxation between successive small perturbations. When larger doses (233 or 582.5 J/m2) of UVB were applied, however, these genes exhibited prolonged down- or up-regulation without relaxation. A cyclic pattern of gene expression following repeated small perturbations indicates the existence of steady states. This cycle pattern is suppressed when large perturbations are applied. In our experiments, the functions of up-regulated genes were mainly associated with anti-proliferation, anti-mitogenesis, and apoptosis. On the other hand, down-regulated genes w (...truncated)


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Ching-Lung Huang, Wun-Yi Shu, Min-Lung Tsai, Chi-Shiun Chiang, Cheng-Wei Chang, Chiu-Ting Chang, Ian C. Hsu. Repeated Small Perturbation Approach Reveals Transcriptomic Steady States, PLOS ONE, 2011, 12, DOI: 10.1371/journal.pone.0029241