Biology Reference
In-Depth Information
(Individual
(epi)
genome)
(t=0; intrinsic susceptibility
to dysregulation)
(Enviromental perturbation)
Sustained, complex perturbations
Perturbation
Network
steady state
(Homeostatic
state)
1) Perturbed network
2) Transitory activation of defense,
stress response networks (-o-)
(e.g., heat-shock, proteostasis)
3) Deactivation of redundant
networks. New homeostatic state
Complex cascade of
networks dysregulations
(downstream progressive dysregulation )
Complex dysregulation
Complex imbalances / diseases
Time
FIGURE 18.3
Dynamics of dysregulation of biological networks towards recovery of homeostatic state and/or cascades of complex dysregu-
lation/imbalances/diseases. The genome and epigenome ('nature') define/underlie the essential networks, homeostatic states and initial suscepti-
bility to dysregulation of an organism, which will be subjected to a specific sequence of environmental perturbations ('nurture') during its lifetime.
Simple/mild perturbations result in transient deactivation of redundant networks and subnetworks (gray nodes and edges) and activation of defense,
stress responses (e.g., heat-shock, protein homeostasis, inflammatory and/or immunological networks; see new nodes and edges, -o- ) until a new
homeostatic state is restored. More importantly, complex (e.g., multifactorial) and/or sustained perturbations overcoming the intrinsic defenses and
stress responses may result in specific sequences/cascades of dysregulations, which propagate towards intertwined essential biological networks,
resulting in highly complex acute imbalances and diseases, with potential collapse of the whole networks system. Periodic, longitudinal monitoring
towards characterization of homeostatic and perturbed networks in different genetic backgrounds in molecular and systems biology comprehensive
experiments in model organisms (i.e., from yeast to human)
[53,93,243]
have the potential to unveil the origin, early stages, and dynamics of
progression of complex imbalances and diseases well before the 'point of no return' (e.g., sequence of dysregulation of essential networks in
neurological diseases and cancers), towards early diagnosis (e.g., characterization of relevant, multiple biomarkers, at different 'omic' levels) and
rational, truly affordable, counteracting and therapeutic strategies. Human interactome network picture visualized by Cytoscape 2.5. Human
microbiome networks
[238]
with direct interactions with the human interactome are omitted for clarity. Dataset created by Andrew Garrow at Unilever
UK. Author: Keiono, reproduced under GNU Free Documentation License and Creative Commons (CC) licenses (
http://en.wikipedia.org/wiki/File:
of recovery of new steady states, or propagation of cascade
effects towards more acute phenotypes; (c) the derivation of
key 'design' principles, universal rules in dynamic
networks, principles of biological circuits, modules, enti-
ties, networks and their interplay
[247,248]
, e.g., 'bimodal
gene expression activation in 'stress inducible genes'
[249]
,
systems-level circuitry principles of the eukaryotic cell
cycle
[250]
; (d) 'humanized' yeast strains can be con-
structed, allowing the 'awesome power' of yeast systems
biology to be brought to bear on the problems of human
disease. As clear examples, such yeast systems biology
studies would be of great interest to advance in the insight
and progression of complex diseases using, among others:
S. cerevisiae cells expressing the oncogene-like RAS2
[251]
; yeast cells expressing human mutant isocitrate
dehydrogenase IDH, producing the oncometabolite
2-hydroxyglutarate (2HG), leading to impairment in
histone demethylation, heterochromatin modifications in
human gliomas and acute myeloid leukemia
[252
254]
for
the study of interdependence of genetic and epigenetic
alterations; yeasts expressing human disease alleles causing
homocystinuria
[255]
; yeast strains with the lipid defect
responsible for Niemann
e
Pick type C (NP-C) disease
[256]
; a yeast model of human protein aggregation in
e
