Deconstructing transcriptional heterogeneity in pluripotent stem cells

Roshan M. Kumar, Patrick Cahan, Alex K. Shalek, Rahul Satija, Ajay Daley Keyser, Hu Li, Jin Zhang, Keith Pardee, David Gennert, John J. Trombetta, Thomas C. Ferrante, Aviv Regev, George Q. Daley, James J. Collins

Research output: Contribution to journalArticle

Abstract

Pluripotent stem cells (PSCs) are capable of dynamic interconversion between distinct substates; however, the regulatory circuits specifying these states and enabling transitions between them are not well understood. Here we set out to characterize transcriptional heterogeneity in mouse PSCs by single-cell expression profiling under different chemical and genetic perturbations. Signalling factors and developmental regulators show highly variable expression, with expression states for some variable genes heritable through multiple cell divisions. Expression variability and population heterogeneity can be influenced by perturbation of signalling pathways and chromatin regulators. Notably, either removal of mature microRNAs or pharmacological blockage of signalling pathways drives PSCs into a low-noise ground state characterized by a reconfigured pluripotency network, enhanced self-renewal and a distinct chromatin state, an effect mediated by opposing microRNA families acting on the Myc/Lin28/let-7 axis. These data provide insight into the nature of transcriptional heterogeneity in PSCs.

Original languageEnglish (US)
Pages (from-to)56-61
Number of pages6
JournalNature
Volume516
Issue number729
DOIs
StatePublished - Dec 4 2014

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Pluripotent Stem Cells
MicroRNAs
Chromatin
Population Characteristics
Cell Division
Noise
Pharmacology
Genes

ASJC Scopus subject areas

  • General

Cite this

Kumar, R. M., Cahan, P., Shalek, A. K., Satija, R., Keyser, A. D., Li, H., ... Collins, J. J. (2014). Deconstructing transcriptional heterogeneity in pluripotent stem cells. Nature, 516(729), 56-61. https://doi.org/10.1038/nature13920

Deconstructing transcriptional heterogeneity in pluripotent stem cells. / Kumar, Roshan M.; Cahan, Patrick; Shalek, Alex K.; Satija, Rahul; Keyser, Ajay Daley; Li, Hu; Zhang, Jin; Pardee, Keith; Gennert, David; Trombetta, John J.; Ferrante, Thomas C.; Regev, Aviv; Daley, George Q.; Collins, James J.

In: Nature, Vol. 516, No. 729, 04.12.2014, p. 56-61.

Research output: Contribution to journalArticle

Kumar, RM, Cahan, P, Shalek, AK, Satija, R, Keyser, AD, Li, H, Zhang, J, Pardee, K, Gennert, D, Trombetta, JJ, Ferrante, TC, Regev, A, Daley, GQ & Collins, JJ 2014, 'Deconstructing transcriptional heterogeneity in pluripotent stem cells', Nature, vol. 516, no. 729, pp. 56-61. https://doi.org/10.1038/nature13920
Kumar RM, Cahan P, Shalek AK, Satija R, Keyser AD, Li H et al. Deconstructing transcriptional heterogeneity in pluripotent stem cells. Nature. 2014 Dec 4;516(729):56-61. https://doi.org/10.1038/nature13920
Kumar, Roshan M. ; Cahan, Patrick ; Shalek, Alex K. ; Satija, Rahul ; Keyser, Ajay Daley ; Li, Hu ; Zhang, Jin ; Pardee, Keith ; Gennert, David ; Trombetta, John J. ; Ferrante, Thomas C. ; Regev, Aviv ; Daley, George Q. ; Collins, James J. / Deconstructing transcriptional heterogeneity in pluripotent stem cells. In: Nature. 2014 ; Vol. 516, No. 729. pp. 56-61.
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