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2015 ; 9
(ä): 23
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Increased robustness of early embryogenesis through collective decision-making by
key transcription factors
#MMPMID26033487
Sharifi-Zarchi A
; Totonchi M
; Khaloughi K
; Karamzadeh R
; Araúzo-Bravo MJ
; Baharvand H
; Tusserkani R
; Pezeshk H
; Chitsaz H
; Sadeghi M
BMC Syst Biol
2015[Jun]; 9
(ä): 23
PMID26033487
show ga
BACKGROUND: Understanding the mechanisms by which hundreds of diverse cell types
develop from a single mammalian zygote has been a central challenge of
developmental biology. Conrad H. Waddington, in his metaphoric "epigenetic
landscape" visualized the early embryogenesis as a hierarchy of lineage
bifurcations. In each bifurcation, a single progenitor cell type produces two
different cell lineages. The tristable dynamical systems are used to model the
lineage bifurcations. It is also shown that a genetic circuit consisting of two
auto-activating transcription factors (TFs) with cross inhibitions can form a
tristable dynamical system. RESULTS: We used gene expression profiles of
pre-implantation mouse embryos at the single cell resolution to visualize the
Waddington landscape of the early embryogenesis. For each lineage bifurcation we
identified two clusters of TFs - rather than two single TFs as previously
proposed - that had opposite expression patterns between the pair of bifurcated
cell types. The regulatory circuitry among each pair of TF clusters resembled a
genetic circuit of a pair of single TFs; it consisted of positive feedbacks among
the TFs of the same cluster, and negative interactions among the members of the
opposite clusters. Our analyses indicated that the tristable dynamical system of
the two-cluster regulatory circuitry is more robust than the genetic circuit of
two single TFs. CONCLUSIONS: We propose that a modular hierarchy of regulatory
circuits, each consisting of two mutually inhibiting and auto-activating TF
clusters, can form hierarchical lineage bifurcations with improved safeguarding
of critical early embryogenesis against biological perturbations. Furthermore,
our computationally fast framework for modeling and visualizing the epigenetic
landscape can be used to obtain insights from experimental data of development at
the single cell resolution.