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Mol Cell. 2014 Jul 17;55(2):319-31. doi: 10.1016/j.molcel.2014.06.029.

Dynamic heterogeneity and DNA methylation in embryonic stem cells.

Author information

  • 1Computation and Neural Systems, California Institute of Technology, Pasadena, CA 91125, USA.
  • 2Division of Biology, California Institute of Technology, Pasadena, CA 91125, USA.
  • 3The Wellcome Trust/Cancer Research UK Gurdon Institute, The Henry Wellcome Building of Cancer and Developmental Biology, University of Cambridge, Tennis Court Road, Cambridge CB2 1QN, UK.
  • 4Division of Biology, California Institute of Technology, Pasadena, CA 91125, USA; Biological Network Modeling Center, California Institute of Technology, Pasadena, CA 91125, USA.
  • 5Program in Biochemistry and Molecular Biophysics and Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
  • 6Howard Hughes Medical Institute and Division of Biology and Department of Applied Physics, California Institute of Technology, Pasadena, CA 91125, USA. Electronic address: melowitz@caltech.edu.

Abstract

Cell populations can be strikingly heterogeneous, composed of multiple cellular states, each exhibiting stochastic noise in its gene expression. A major challenge is to disentangle these two types of variability and to understand the dynamic processes and mechanisms that control them. Embryonic stem cells (ESCs) provide an ideal model system to address this issue because they exhibit heterogeneous and dynamic expression of functionally important regulatory factors. We analyzed gene expression in individual ESCs using single-molecule RNA-FISH and quantitative time-lapse movies. These data discriminated stochastic switching between two coherent (correlated) gene expression states and burst-like transcriptional noise. We further showed that the "2i" signaling pathway inhibitors modulate both types of variation. Finally, we found that DNA methylation plays a key role in maintaining these metastable states. Together, these results show how ESC gene expression states and dynamics arise from a combination of intrinsic noise, coherent cellular states, and epigenetic regulation.

Copyright © 2014 Elsevier Inc. All rights reserved.

PMID:
25038413
[PubMed - indexed for MEDLINE]
PMCID:
PMC4104113
Free PMC Article
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