title: Increased robustness of early embryogenesis through collective decision-making by key transcription factors.
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.
authors.affiliation: Department of Bioinformatics, Institute of Biochemistry and Biophysics, University of Tehran, Tehran, Iran. a.sharifi@ibb.ut.ac.ir.|Department of Stem Cells and Developmental Biology at Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran. a.sharifi@ibb.ut.ac.ir.|Computer Science Department, Colorado State University, Fort Collins, Colorado, 80523, USA. a.sharifi@ibb.ut.ac.ir.
authors.forename: Ali
authors.initials: A
authors.lastname: Sharifi-Zarchi
authors.affiliation: Department of Stem Cells and Developmental Biology at Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran. totonchimehdi@gmail.com.|Department of Genetics at Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran. totonchimehdi@gmail.com.
authors.forename: Mehdi
authors.initials: M
authors.lastname: Totonchi
authors.affiliation: Department of Stem Cells and Developmental Biology at Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran. keynoosh_khalooghi@yahoo.com.
authors.forename: Keynoush
authors.initials: K
authors.lastname: Khaloughi
authors.affiliation: Department of Stem Cells and Developmental Biology at Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran. razieh.karamzadeh@gmail.com.|Department of Biophysics, Institute of Biochemistry and Biophysics, University of Tehran, Tehran, Iran. razieh.karamzadeh@gmail.com.
authors.forename: Razieh
authors.initials: R
authors.lastname: Karamzadeh
authors.affiliation: Computational Biology and Bioinformatics Group, Max Planck Institute for Molecular Biomedicine, Münster, Germany. mararabra@yahoo.co.uk.|Group of Computational Biology and Systems Biomedicine, Biodonostia Health Research Institute, 20014, San Sebastián, Spain. mararabra@yahoo.co.uk.|IKERBASQUE, Basque Foundation for Science, 48011, Bilbao, Spain. mararabra@yahoo.co.uk.
authors.forename: Marcos J
authors.initials: MJ
authors.lastname: Araúzo-Bravo
authors.affiliation: Department of Stem Cells and Developmental Biology at Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran. Baharvand@royaninstitute.org.
authors.forename: Hossein
authors.initials: H
authors.lastname: Baharvand
authors.affiliation: School of Computer Science, Institute for Research in Fundamental Sciences, Tehran, Iran. ruztus@yahoo.com.
authors.forename: Ruzbeh
authors.initials: R
authors.lastname: Tusserkani
authors.affiliation: School of Mathematics, Statistics and Computer Sciences, Center of Excellence in Biomathematics, College of Science, University of Tehran, Tehran, Iran. pezeshk@khayam.ut.ac.ir.|School of Biological Science, Institute for Research in Fundamental Sciences (IPM), Tehran, Iran. pezeshk@khayam.ut.ac.ir.
authors.forename: Hamid
authors.initials: H
authors.lastname: Pezeshk
authors.affiliation: Computer Science Department, Colorado State University, Fort Collins, Colorado, 80523, USA. chitsaz@chitsazlab.org.
authors.forename: Hamidreza
authors.initials: H
authors.lastname: Chitsaz
authors.affiliation: School of Biological Science, Institute for Research in Fundamental Sciences (IPM), Tehran, Iran. sadeghi@nigeb.ac.ir.|National Institute of Genetic Engineering and Biotechnology (NIGEB), Tehran, Iran. sadeghi@nigeb.ac.ir.
authors.forename: Mehdi
authors.initials: M
authors.lastname: Sadeghi
mesh_terms: D000818:Animals; D001755:Blastocyst / Q000166:cytology / Q000378:metabolism; D047108:Embryonic Development; D020869:Gene Expression Profiling; D051379:Mice; D008954:Models, Biological; D059010:Single-Cell Analysis; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D014157:Transcription Factors