Increased robustness of early embryogenesis through collective decision-making by key transcription factors

BMC Systems Biology

Mehdi Sadeghi²  Hamidreza Chitsaz³  Hamid Pezeshk⁶  Ruzbeh Tusserkani⁵  Hossein Baharvand⁴  Marcos J. Araúzo-Bravo⁸  Razieh Karamzadeh¹  Keynoush Khaloughi⁴  Mehdi Totonchi⁷  Ali Sharifi-Zarchi⁴ 

[1] Department of Biophysics, Institute of Biochemistry and Biophysics, University of Tehran, Tehran, Iran;National Institute of Genetic Engineering and Biotechnology (NIGEB), Tehran, Iran;Computer Science Department, Colorado State University, Fort Collins 80523, Colorado, USA;Department of Stem Cells and Developmental Biology at Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran;School of Computer Science, Institute for Research in Fundamental Sciences, Tehran, Iran;School of Mathematics, Statistics and Computer Sciences, Center of Excellence in Biomathematics, College of Science, University of Tehran, Tehran, Iran;Department of Genetics at Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran;IKERBASQUE, Basque Foundation for Science, Bilbao, 48011, Spain

关键词: Single cell analysis;    Genetic circuit;    Developmental bifurcations;    Differentiation;    Early embryogenesis;    Waddington landscape;   

Others  :  1210171
DOI  :  10.1186/s12918-015-0169-8

 received in 2014-08-15, accepted in 2015-05-15,  发布年份 2015

【 摘 要 】

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.

【 授权许可】

   
2015 Sharifi-Zarchi et al.; licensee BioMed Central.

【 图 表 】

Fig. 1.

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Fig. 7.

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