Gene networks of fully connected triads with complete auto-activation enable multistability and stepwise stochastic transitions

Philippe C. Faucon, Keith Pardee, Roshan M. Kumar, Hu Li, Yuin Han Loh, Xiao Wang

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

Fully-connected triads (FCTs), such as the Oct4-Sox2-Nanog triad, have been implicated as recurring transcriptional motifs embedded within the regulatory networks that specify and maintain cellular states. To explore the possible connections between FCT topologies and cell fate determinations, we employed computational network screening to search all possible FCT topologies for multistability, a dynamic property that allows the rise of alternate regulatory states from the same transcriptional network. The search yielded a hierarchy of FCTs with various potentials for multistability, including several topologies capable of reaching eight distinct stable states. Our analyses suggested that complete auto-activation is an effective indicator for multistability, and, when gene expression noise was incorporated into the model, the networks were able to transit multiple states spontaneously. Different levels of stochasticity were found to either induce or disrupt random state transitioning with some transitions requiring layovers at one or more intermediate states. Using this framework we simulated a simplified model of induced pluripotency by including constitutive overexpression terms. The corresponding FCT showed random state transitioning from a terminal state to the pluripotent state, with the temporal distribution of this transition matching published experimental data. This work establishes a potential theoretical framework for understanding cell fate determinations by connecting conserved regulatory modules with network dynamics. Our results could also be employed experimentally, using established developmental transcription factors as seeds, to locate cell lineage specification networks by using auto-activation as a cipher.

Original languageEnglish (US)
Article numbere102873
JournalPLoS One
Volume9
Issue number7
DOIs
StatePublished - Jul 24 2014

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Gene Regulatory Networks
automobiles
topology
Genes
Chemical activation
Topology
Cell Lineage
Noise
Seeds
Transcription Factors
cells
Gene Expression
Gene expression
Seed
Screening
transcription factors
screening
Specifications
gene expression
seeds

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Gene networks of fully connected triads with complete auto-activation enable multistability and stepwise stochastic transitions. / Faucon, Philippe C.; Pardee, Keith; Kumar, Roshan M.; Li, Hu; Loh, Yuin Han; Wang, Xiao.

In: PLoS One, Vol. 9, No. 7, e102873, 24.07.2014.

Research output: Contribution to journalArticle

Faucon, Philippe C. ; Pardee, Keith ; Kumar, Roshan M. ; Li, Hu ; Loh, Yuin Han ; Wang, Xiao. / Gene networks of fully connected triads with complete auto-activation enable multistability and stepwise stochastic transitions. In: PLoS One. 2014 ; Vol. 9, No. 7.
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