Mori-Grant report / Fisical year 2008.

Vincent PIRAS

Keio University - Graduate School of Media and Governance - Systems Biology program - Systems Immunology group
Address: Keio University, Institute for Advanced Biosciences TTCK 14-1 baba-cho, Tsuruoka, Yamagata 997-0035 Japan

Research project: Systems biology approach for the Understanding of Innate Immune mechanism

Term report


Emergent genome-wide control in wildtype and genetically mutated lipopolysaccarides-stimulated macrophages

Masa Tsuchiya1,2#˜, Vincent Piras1,2#, Sangdun Choi3, Shizuo Akira4, Masaru Tomita1,2, Alessandro Giuliani5 & Kumar Selvarajoo1,2#˜

1 Institute for Advanced Biosciences, Keio University, Tsuruoka, 997-0035, Japan.
2 Systems Biology Program, School of Media and Governance, Keio University, Fujisawa, 252-8520, Japan.
3 Department of Molecular Science and Technology, Ajou University, Suwon, 443-749, Korea.
4 Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Osaka, 565-0871, Japan.
5 Istituto Superiore di Sanitaf, Environment and Health Department, Rome, 00161, Italy.

# Equal contributions
˜ Co-corresponding authors


Large-scale gene expression studies have mainly focused on highly expressed and ediscriminatoryf genes to decipher key regulatory processes. Biological responses are consequence of the concerted action of gene regulatory network, thus, limiting our attention to genes having the most significant variations is insufficient for a thorough understanding of emergent whole genome response. Here we comprehensively analyzed the temporal oligonucleotide microarray data of lipopolysaccharide (LPS) stimulated macrophages in 4 genotypes; wildtype, Myeloid Differentiation factor 88 (MyD88) knockout (KO), TIR-domain-containing adapter-inducing interferon-ƒÀ (TRIF) KO and MyD88/TRIF double KO (DKO). Pearson correlations computed on the whole genome expression between different genotypes are extremely high (> 0.98), indicating a strong co-regulation of the entire expression network. Further correlation analyses reveal genome-wide response is biphasic, i) acute-stochastic mode consisting of small number of sharply induced immune-related genes and ii) collective mode consisting of majority of weakly induced genes of diverse cellular processes which collectively adjust their expression level. Notably, temporal correlations of a small number of randomly selected genes from collective mode show scalability. Furthermore, in collective mode, the transition from large scatter in expression distributions for single ORFs to smooth linear lines emerges as an organizing principle when grouping of 50 ORFs and above. With this emergent behavior, the role of MyD88, TRIF and novel MyD88, TRIF-independent processes for gene induction can be linearly superposed to decipher quantitative whole genome differential control of transcriptional and mRNA decay machineries. Our work demonstrates genome-wide co-regulated responses subsequent to specific innate immune stimulus which have been largely neglected.

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(This article has been accepted for publication at Plos ONE)

Local and global responses in complex gene regulation networks

Masa Tsuchiya1,#, Kumar Selvarajoo1,#, Vincent Piras1, Masaru Tomita1 and Alessandro Giuliani2

# Equal contributions
˜ corresponding authors

1 Institute for Advanced Biosciences, Keio University, Tsuruoka, 997-0035, Japan.
2 Istituto Superiore di Sanitaf, Environment and Health Department, Rome, 00161, Italy.


An exacerbated sensitivity to apparently minor stimuli and a general resilience of the entire system stay together side-by-side in biological systems. This apparent paradox can be explained by the consideration of biological systems as very strongly interconnected network systems. Some nodes of these networks, thanks to their peculiar location in the network architecture, are responsible for the sensitivity aspects, while the large degree of interconnection is at the basis of the resilience properties of the system.
One relevant feature of the high degree of connectivity of gene regulation networks is the emergence of collective ordered phenomena influencing the entire genome and not only a specific portion of transcripts. The great majority of existing gene regulation models give the impression of purely local ehard-wiredf mechanisms disregarding the emergence of global ordered behavior encompassing thousands of genes while the general, genome wide, aspects are less known.
Here we address, on a data analysis perspective, the discrimination between local and global scale regulations, this goal was achieved by means of the examination of two biological systems: innate immune response in macrophages and oscillating growth dynamics in yeast. Our aim was to reconcile the ehard-wiredf local view of gene regulation with a global continuous and scalable one borrowed from statistical physics. This reconciliation is based on the network paradigm in which the local ehard-wiredf activities correspond to the activation of specific crucial nodes in the regulation network, while the scalable continuous responses can be equated to the collective oscillations of the network after a perturbation.

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(This article has been published at Physica A journal)