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’, Environment and Health Department, Rome, 00161,
Italy.
# Equal
contributions
§ Co-corresponding authors
Abstract
Large-scale gene
expression studies have mainly focused on highly expressed and ‘discriminatory’
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-β (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.
(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’, Environment and Health Department, Rome, 00161,
Italy.
Abstract
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 ‘hard-wired’ 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 ‘hard-wired’ 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
‘hard-wired’ 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.
(This article has been published at Physica A journal)