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.
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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)