284902 Robustness and Energetic Analysis of an Extended Pluripotency MODEL of Embryonic STEM CELLS Transcriptional Network

Wednesday, October 31, 2012: 10:18 AM
Westmoreland Central (Westin )
Deepak Nagrath, Department of Chemical Engineering, Rice University, Houston, TX, Marco Avila, Massachusetts General Hospital/Shriners Burn Hospital/Harvard Medical School, Boston, MA and Martin L. Yarmush, Center for Engineering in Medicine, MGH/Harvard Medical School, Boston, MA

Embryonic stem cells (ESCs) are pluripotent because they can give rise to cells derived from all three germ layers. ESCs are considered a potential source of cells for human disease therapies due to their limitless capacity for self-renewal and proliferation, and their ability to differentiate into all major cell lineages. Octamer-4 (Oct4), Sox2 and Nanog are important markers of pluripotency, expressed by primitive embryonic cells both in vivo and in vitro. Oct4 and Nanog expression is downregulated during early differentiation. In embryonic stem cells (ESCs), the stem cell-ness is determined by the expression of three major transcription factors: Oct4, Sox2 and Nanog.

The transcriptional regulatory network model for pluripotency of embryonic stem cells consists of various autoregulatory, feedback and feedforward loops, single input modules and bifan motifs. The ESC regulatory network as seen in figure has multilevel network architecture. It can be divided into three levels: (1) Level-0, transcriptional regulatory circuit with three transcription factors Oct4, Sox2 and Nanog; (2) Level-1, inner core of transcriptional circuity with nine transcription factors Klf4, c-Myc, Zfp281, Sox2, Nanog, Oct4, Rex1, Dax1 and Nac1; and (3) Level-2, combined transcriptional regulatory circuit with target hubs of multiple transcription factors.

Not much has been understood about the occurrence of these motifs and levels in embryonic stem cells network biology. Thus, there has been lack of explanation on how a level architecture in ESC network influences other levels, functional role of various levels, dynamics and functional objectives of ESCs TRN. Moreover, there has been the lack of a regulatory network analysis criterion which can describe the underlying mechanisms behind the occurrence of these layers, motifs, as well as the way in which these motifs play a role in developmental biology and the way that both functional objectives and topological architecture may evolve.

Here, we postulate that the architecture of ESC-TRN can be explained based on a conceptual framework that integrates nonequilibrium thermodynamics with Pareto-optimality of the biological functions to be carried out by the embryonic stem cells. We present an energetic-cost theory that can explain cofactor occupancy as well as the topological arrangement of the ESC network. Through the developed framework, we have tried to answer the questions of why during development certain architecture is favored and what advantage different levels offer for steady state analyses. Our study also demonstrates that ESC network analyses using often-ignored energetics enables identification of new functionalities for various topological arrangements.

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