Transcript Test system for systems biology

Test system for systems biology
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Four distinct types of global datasets were
generated and analyzed
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Proteome analysis quantitative proteomics (ICAT
technology) to analyze 300 proteins in wild-type yeast
with the system turned on and off
① Thirty of these proteins changed in the transition
between these two biological states
② the mRNA and protein changes went in different
directions for 15 of these examples
post-transcription control mechanisms must
regulate protein synthesis in half of the
examples
Test system for systems biology
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Four distinct types of global datasets
were generated and analyzed
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Kinetic analysis of global mRNA concentrations
change across the physiological time span of
activation of the galactose biomodule
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Kinetic data provide powerful new approaches
to understanding the temporal operation of the
galactose biomodule and its temporal
connections to other biomodules in the yeast
cell
Test system for systems biology
• Endomesodermal development in sea
urchin
1. The architecture of a gene regulatory network is
specified by the DNA binding sites, for these
establish the linkages of the transcription factors
that coordinate the behaviors of genes throughout
the gene regulatory networks.
2. The gene regulatory networks contribute to
determine the behavior of the peripheral (structural)
genes in the network.
3. The peripheral genes ultimately execute the specific
development functions that underlie particular
aspects of development.
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The green
panel depicts
primarily
transcription
factors and
their
interactions
with the control
regions of
other
transcription
factors.
Genes are
indicated by
horizontal lines.
Arrowheads
indicate
activation.
I indicate
repression
The yellow
(lower) panel
indicates
peripheral
genes that
carry out the
functions of
endodermal
development.
• The 2.1-kb promoter region of the endo16 gene is
enlarged here and depicts 34 DNA binding sites
(rectangles) and 13 different transcription factors and
cofactors (rectangles or lollipops connected by lines
to the DNA binding sites).
• Experiments indicate that there are six modules (A–G)
that carry out discrete functions for the
developmental regulation of endo 16.
• The ultimate objective is to convert this logic diagram
into a mathematical formulation that accurately
represents the subtle complexities of this
developmental circuit.
• A logical diagram depicting the functions
of the A and B modules throughout
endomesodermal development.
• This logic then embodies a mathematical
relationship between the control segments.
Host–pathogen systems biology
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For tryptophan biosynthesis C. psittaci
obtains an alternative source of anthranilate
by hijacking the host’s tryptophan depletion
pathway by intercepting the byproduct
kynurenine.
1. the tryptophan depletion pathway of the host is
activated by inducing indoleamine-2,3-dioxygenase
using IFN-γ
2. C. psittaci uses host kynurenine through kynU to
produce its own tryptophan, enabling intracellular
growth and causing chronic infections.
Host–pathogen systems biology
• Group A Streptococcus, the causative agent of mild
infections and life-threatening invasive diseases,
produces many virulence factors that promote
survival in humans.
• A two component regulatory system, designated covRS
(cov, control of virulence; csrRS), negatively controls
expression of five proven or putative virulence factors
(capsule, cysteine protease, streptokinase, streptolysin S,
and streptodornase)
• Inactivation of covRS results in enhanced virulence in
mouse models of invasive disease
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GAS CovR gene regulation network delineated by microarray expression analysis. CovRS respond
to unknown environmental signals and modulate expression of several broad categories of GAS
genes involved in growth and adaptation by a phosphorelay mechanism. CovR-regulated gene
products influence host–pathogen interactions, including capsular polysaccharide (capsule), cell
proteins anchored via LPXTG motifs (surface proteins), cytosolic and membrane proteins involved
in environmental adaptation (adaptation response), and extracellular proteins containing secretion
signals (secreted proteins).
Several two-component systems (ovals) and other transcriptional regulators (squares) are also
CovR-regulated, but their downstream regulatory consequences are unknown. Red lines, downregulation; green lines, up-regulation. PG, peptidoglycan; , secreted proteins; surface solid
rectangles, secreted proteins with LPXTG motifs. Numbers denote SPy numbers assigned for
serotype M1 GAS strain SF370 ORFs.
Host–pathogen systems biology
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Systems biology in malaria research
integrating genomics, transcriptomics
and proteomics, we can
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classify and annotate genes by their expression
profiles
detect evidence of posttranscriptional gene
silencing in the murine malaria species.
Metabolic pathway reconstruction by expression
analysis
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Metabolic pathway reconstruction by expression analysis.
(a) Table showing representation of protein expression from the glycolytic and TCA
pathways, color coded by protein sequence coverage identified through proteomics
experiments (see key). The sequence coverage values in the table serve as a crude
measurement of protein abundance. Values are from Ref. [1]. During asexual blood
stages, the glycolytic pathway is active, resulting in the production of lactate, whereas
there is no evidence of a complete TCA cycle during these stages.
(b) Pathway glyph representation of the activity of metabolic pathways, as determined
by their proteomics expression profiles.Red indicates active pathways and gray
indicates inactive pathways.
Host–pathogen systems biology
• Systems biology in Schistosoma research
integrating genomics,
transcriptomics and proteomics
• Reconstruction and in silico analysis of the
MAPK and WNT signaling pathways in
Schistosoma japonicum
MAPK signaling pathways regulating
proliferation and differentiation processes
in Schistosoma
Host–pathogen systems biology
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The global molecular interaction
architecture of the immune system
1. molecular interactions of the immune
system actually consist of a nested
tandem bow-tie architecture
2. This architecture can be recognized
both in intracellular signal
transduction pathways and in
intercellular signaling processes
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Nested bow-tie architecture in immune system. Salient features of the
immune system network are nested bow-tie structures and extensive
feedback loops. The bow-tie structure of intercellular interactions
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The bow-tie architecture also exists at the signal transduction level
Future directions or open issues in
systems biology
1. Nanotechnology
2. integration across disciplines
3. Modeling