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

197 Scopus citations

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

ASJC Scopus subject areas

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    Kumar, R. M., Cahan, P., Shalek, A. K., Satija, R., Keyser, A. D., Li, H., Zhang, J., Pardee, K., Gennert, D., Trombetta, J. J., Ferrante, T. C., Regev, A., Daley, G. Q., & Collins, J. J. (2014). Deconstructing transcriptional heterogeneity in pluripotent stem cells. Nature, 516(729), 56-61. https://doi.org/10.1038/nature13920