title: Deconstructing transcriptional heterogeneity in pluripotent stem cells.
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.
authors.affiliation: Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, Massachusetts 02115, USA.|Howard Hughes Medical Institute, Department of Biomedical Engineering, Center of Synthetic Biology, Boston University, Boston, Massachusetts 02215, USA.
authors.forename: Roshan M
authors.initials: RM
authors.lastname: Kumar
authors.affiliation: Stem Cell Transplantation Program, Division of Pediatric Hematology and Oncology, Manton Center for Orphan Disease Research, Howard Hughes Medical Institute, Boston Children's Hospital and Dana Farber Cancer Institute, Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Harvard Stem Cell Institute, Boston, Massachusetts 02115, USA.
authors.forename: Patrick
authors.initials: P
authors.lastname: Cahan
authors.affiliation: Department of Chemistry and Chemical Biology and Department of Physics, Harvard University, 12 Oxford Street, Cambridge, Massachusetts 02138, USA.
authors.forename: Alex K
authors.initials: AK
authors.lastname: Shalek
authors.affiliation: Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, Massachusetts 02142, USA.
authors.forename: Rahul
authors.initials: R
authors.lastname: Satija
authors.affiliation: Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, Massachusetts 02115, USA.
authors.forename: AJay
authors.initials: A
authors.lastname: DaleyKeyser
authors.affiliation: Center for Individualized Medicine, Department of Molecular Pharmacology & Experimental Therapeutics, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA.
authors.forename: Hu
authors.initials: H
authors.lastname: Li
authors.affiliation: Stem Cell Transplantation Program, Division of Pediatric Hematology and Oncology, Manton Center for Orphan Disease Research, Howard Hughes Medical Institute, Boston Children's Hospital and Dana Farber Cancer Institute, Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Harvard Stem Cell Institute, Boston, Massachusetts 02115, USA.
authors.forename: Jin
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, Massachusetts 02115, USA.|Howard Hughes Medical Institute, Department of Biomedical Engineering, Center of Synthetic Biology, Boston University, Boston, Massachusetts 02215, USA.
authors.forename: Keith
authors.initials: K
authors.lastname: Pardee
authors.affiliation: Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, Massachusetts 02142, USA.
authors.forename: David
authors.initials: D
authors.lastname: Gennert
authors.affiliation: Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, Massachusetts 02142, USA.
authors.forename: John J
authors.initials: JJ
authors.lastname: Trombetta
authors.affiliation: Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, Massachusetts 02115, USA.
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Ferrante
authors.affiliation: Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, Massachusetts 02142, USA.|Howard Hughes Medical Institute, Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02140, USA.
authors.forename: Aviv
authors.initials: A
authors.lastname: Regev
authors.affiliation: Stem Cell Transplantation Program, Division of Pediatric Hematology and Oncology, Manton Center for Orphan Disease Research, Howard Hughes Medical Institute, Boston Children's Hospital and Dana Farber Cancer Institute, Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Harvard Stem Cell Institute, Boston, Massachusetts 02115, USA.
authors.forename: George Q
authors.initials: GQ
authors.lastname: Daley
authors.affiliation: Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, Massachusetts 02115, USA.|Howard Hughes Medical Institute, Department of Biomedical Engineering, Center of Synthetic Biology, Boston University, Boston, Massachusetts 02215, USA.
authors.forename: James J
authors.initials: JJ
authors.lastname: Collins
mesh_terms: D000818:Animals; D016923:Cell Death; D002455:Cell Division; D053595:Embryonic Stem Cells / Q000166:cytology / Q000502:physiology; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D051379:Mice; D035683:MicroRNAs / Q000378:metabolism; D039904:Pluripotent Stem Cells / Q000166:cytology / Q000502:physiology*; D015398:Signal Transduction
chemical_list: D035683:MicroRNAs