Dynamical Reorganization of Transcriptional Events Governs Robust Nanog Heterogeneity.

Tagari Samanta,Sandip Kar

doi:10.1021/acs.jpcb.9b03411

Abstract

Nanog maintains the pluripotency of embryonic stem cells (ESCs), while demonstrating high expression heterogeneity. Intriguingly, the overall heterogeneity at the Nanog mRNA level under various culture conditions gets precisely partitioned into intrinsic and extrinsic fluctuations. However, the dynamical origin of such a robust transcriptional noise regulation still remains illusive. Herein, we propose a new stochastic simulation strategy that efficiently reconciles the strict apportioning of fluctuations observed in Nanog transcription, while predicting possible experimental scenarios to avoid such an exact noise segregation. Importantly, our model analyses reveal that different culture conditions essentially preserve the robust Nanog expression heterogeneity by altering the dynamics of transcriptional events. In the future, these insights will be useful to systematically maneuver cell-fate decision-making events of ESCs.

Highlights

Embryonic stem cells (ESCs) have a unique ability to either maintain their stemness via selfrenewal or differentiate into a particular cell-type under specific growth conditions (Hyslop et al, 2005; Lie et al, 2012; Young, 2011)
We optimized the network in such a way that we could reproduce total number of Nanog mRNA under different culture conditions as measured by Ochiai et al (Ochiai et al, 2014)
It is important to note that in our simulations, we have not been able to reproduce the absolute values of different noise levels, as observed experimentally, but our stochastic simulations capture the essential features and trends of the Nanog transcriptional noise regulation

Summary

Introduction

Embryonic stem cells (ESCs) have a unique ability to either maintain their stemness via selfrenewal or differentiate into a particular cell-type under specific growth conditions (Hyslop et al, 2005; Lie et al, 2012; Young, 2011). ESC’s will be highly relevant for developing stem cell based treatment strategies, provided, we figure out how to tune the specific cell fate determining molecular regulators of ESC’s by altering the culture conditions precisely. Among these molecular regulators, Nanog (a transcription factor) plays a decisive role (Ambrosetti et al, 2000; Boyer et al, 2006; Loh et al, 2006; Macarthur et al, 2013; Mitsui et al, 2003; Niwa, 2007). A higher level of Nanog expression maintains ESC’s in a pluripotent like state, whereas ESC’s expressing low levels of Nanog are more prone to differentiate (Chambers et al, 2007; Fischer et al, 2010; Glauche et al, 2010; Kalmar et al, 2009; Singh et al, 2007). It is imperative to investigate how fluctuations, at the first place, influence the Nanog transcriptional events to orchestrate the Nanog expression heterogeneity

Methods

Results

Conclusion