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| Paper IPM / Biological Sciences / 13897 |
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Abstract
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
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