Dynamic heterogeneity and DNA methylation in embryonic stem cells.

Handle URI:
http://hdl.handle.net/10754/596781
Title:
Dynamic heterogeneity and DNA methylation in embryonic stem cells.
Authors:
Singer, Zakary S; Yong, John; Tischler, Julia; Hackett, Jamie A; Altinok, Alphan; Surani, M Azim; Cai, Long; Elowitz, Michael B
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.
Citation:
Singer ZS, Yong J, Tischler J, Hackett JA, Altinok A, et al. (2014) Dynamic Heterogeneity and DNA Methylation in Embryonic Stem Cells. Molecular Cell 55: 319–331. Available: http://dx.doi.org/10.1016/j.molcel.2014.06.029.
Publisher:
Elsevier BV
Journal:
Molecular Cell
Issue Date:
1-Jul-2014
DOI:
10.1016/j.molcel.2014.06.029
PubMed ID:
25038413
PubMed Central ID:
PMC4104113
Type:
Article
ISSN:
1097-2765
Sponsors:
We thank Jordi Garcia-Ojalvo, Xiling Shen, Georg Seelig, Arjun Raj, and David Sprinzak for helpful comments on the manuscript; the Kathrin Plath Lab, the Austin Smith Lab, and RIKEN for kindly providing reporter and knockout cell lines; and the Caltech FACS Facility for assistance with cell sorting. This work was supported by the National Institutes of Health grants R01HD075605A, R01GM086793A, and P50GM068763; the Weston Havens Foundation; Human Frontiers Science Program; the Packard Foundation; a Wellcome Trust Investigators Grant to M. A. S.; and a KAUST, APART, and CIRM Fellowship to J.T. This work is funded by the Gordon and Betty Moore Foundation through Grant GBMF2809 to the Caltech Programmable Molecular Technology Initiative.
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Full metadata record

DC FieldValue Language
dc.contributor.authorSinger, Zakary Sen
dc.contributor.authorYong, Johnen
dc.contributor.authorTischler, Juliaen
dc.contributor.authorHackett, Jamie Aen
dc.contributor.authorAltinok, Alphanen
dc.contributor.authorSurani, M Azimen
dc.contributor.authorCai, Longen
dc.contributor.authorElowitz, Michael Ben
dc.date.accessioned2016-02-21T08:50:33Zen
dc.date.available2016-02-21T08:50:33Zen
dc.date.issued2014-07-01en
dc.identifier.citationSinger ZS, Yong J, Tischler J, Hackett JA, Altinok A, et al. (2014) Dynamic Heterogeneity and DNA Methylation in Embryonic Stem Cells. Molecular Cell 55: 319–331. Available: http://dx.doi.org/10.1016/j.molcel.2014.06.029.en
dc.identifier.issn1097-2765en
dc.identifier.pmid25038413en
dc.identifier.doi10.1016/j.molcel.2014.06.029en
dc.identifier.urihttp://hdl.handle.net/10754/596781en
dc.description.abstractCell 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.en
dc.description.sponsorshipWe thank Jordi Garcia-Ojalvo, Xiling Shen, Georg Seelig, Arjun Raj, and David Sprinzak for helpful comments on the manuscript; the Kathrin Plath Lab, the Austin Smith Lab, and RIKEN for kindly providing reporter and knockout cell lines; and the Caltech FACS Facility for assistance with cell sorting. This work was supported by the National Institutes of Health grants R01HD075605A, R01GM086793A, and P50GM068763; the Weston Havens Foundation; Human Frontiers Science Program; the Packard Foundation; a Wellcome Trust Investigators Grant to M. A. S.; and a KAUST, APART, and CIRM Fellowship to J.T. This work is funded by the Gordon and Betty Moore Foundation through Grant GBMF2809 to the Caltech Programmable Molecular Technology Initiative.en
dc.publisherElsevier BVen
dc.rightsThis is an open access article under the CC BY license (http://creativecommons.org/licenses/by/3.0/).en
dc.rights.urihttp://creativecommons.org/licenses/by/3.0/en
dc.subject.meshDNA Methylationen
dc.subject.meshTranscriptomeen
dc.titleDynamic heterogeneity and DNA methylation in embryonic stem cells.en
dc.typeArticleen
dc.identifier.journalMolecular Cellen
dc.identifier.pmcidPMC4104113en
dc.contributor.institutionComputation and Neural Systems, California Institute of Technology, Pasadena, CA 91125, USA.en
dc.contributor.institutionDivision of Biology, California Institute of Technology, Pasadena, CA 91125, USA.en
dc.contributor.institutionThe 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.en
dc.contributor.institutionDivision of Biology, California Institute of Technology, Pasadena, CA 91125, USA; Biological Network Modeling Center, California Institute of Technology, Pasadena, CA 91125, USA.en
dc.contributor.institutionProgram in Biochemistry and Molecular Biophysics and Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA 91125, USA.en
dc.contributor.institutionHoward 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.en

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