Test system for systems biology

• Four distinct types of global datasets were generated and analyzed

1. 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

• Four distinct types of global datasets were generated and analyzed

4. Kinetic analysis of global mRNA concentrations change across the physiological time span of activation of the galactose biomodule

• 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

• 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.

Test system for systems biology

• 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

• 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

• 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, down-regulation; 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

• Systems biology in malaria research integrating genomics, transcriptomics and proteomics, we can

1. classify and annotate genes by their expression profiles

2. detect evidence of posttranscriptional gene silencing in the murine malaria species.

3. Metabolic pathway reconstruction by expression analysis

• Metabolic pathway reconstruction by expression analysis.• (a) Table showing representation of protein expression from the glycolytic and TCA pa

thways, 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

• 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

• 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

• 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