Cell Response to Biological Regulators and Noxious Agents: Attractor States and Constrained Dynamics of Gene Expression Profiles

摘要

Cells and tissues respond to physiological signals and noxious agents by a coordinated genome-wide change of their gene expression profile which in turn controls the switch between 'cellular programs', such as proliferation, differentiation and apoptosis. Characterization of such responses is crucial for civil and defense health purposes (toxicology assessment of novel agents, stem cell control) but typically remains descriptive. No formalism exists to explain dose-response relationship - hampering the understanding of paradoxical effects of low-dose perturbations, such as hormesis. In this project a formal framework was introduced based on two central notions: (l) cell programs, notably the state of differentiation, are attractor states in the high-dimensional state space of genomic regulatory networks, and (2) clonal populations of cells are heterogeneous, hence cells occupy an attractor as a 'cloud'. Experimental analysis in multipotent cells revealed that heterogeneity is due to slow transcriptome fluctuations within attractors, generating, metastable 'outlier' cells that are differentially 'primed' to respond to particular perturbations. This explains their qualitatively distinct responses to low doses and provides a unifying concept for multipotency of stem cells. The results will benefit efforts in reprogramming stem cells and in the analysis of the differential effect of varying doses of drugs and toxins on cell behavior.