Deconstructing transcriptional heterogeneity in pluripotent stem cells

Roshan M. Kumar, Patrick Cahan, Alex K. Shalek, Rahul Satija, A. Jay DaleyKeyser, Hu Li, Jin Zhang, Keith Pardee, David Gennert, John J. Trombetta, Thomas C. Ferrante, Aviv Regev, George Q. Daley () and James J. Collins ()
Additional contact information
Roshan M. Kumar: Wyss Institute for Biologically Inspired Engineering, Harvard University
Patrick Cahan: Stem Cell Transplantation Program, Manton Center for Orphan Disease Research, Howard Hughes Medical Institute, Boston Children’s Hospital and Dana Farber Cancer Institute, Harvard Medical School, Harvard Stem Cell Institute
Alex K. Shalek: Harvard University, 12 Oxford Street, Cambridge, Massachusetts 02138, USA
Rahul Satija: Broad Institute of MIT and Harvard, 7 Cambridge Center
A. Jay DaleyKeyser: Wyss Institute for Biologically Inspired Engineering, Harvard University
Hu Li: Center for Individualized Medicine, Mayo Clinic College of Medicine
Jin Zhang: Stem Cell Transplantation Program, Manton Center for Orphan Disease Research, Howard Hughes Medical Institute, Boston Children’s Hospital and Dana Farber Cancer Institute, Harvard Medical School, Harvard Stem Cell Institute
Keith Pardee: Wyss Institute for Biologically Inspired Engineering, Harvard University
David Gennert: Broad Institute of MIT and Harvard, 7 Cambridge Center
John J. Trombetta: Broad Institute of MIT and Harvard, 7 Cambridge Center
Thomas C. Ferrante: Wyss Institute for Biologically Inspired Engineering, Harvard University
Aviv Regev: Broad Institute of MIT and Harvard, 7 Cambridge Center
George Q. Daley: Stem Cell Transplantation Program, Manton Center for Orphan Disease Research, Howard Hughes Medical Institute, Boston Children’s Hospital and Dana Farber Cancer Institute, Harvard Medical School, Harvard Stem Cell Institute
James J. Collins: Wyss Institute for Biologically Inspired Engineering, Harvard University

Nature, 2014, vol. 516, issue 7529, 56-61

Abstract: 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.

Date: 2014
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DOI: 10.1038/nature13920

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