Deconstructing transcriptional heterogeneity in pluripotent stem cells.

Nature
Authors
Keywords
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.

Year of Publication
2014
Journal
Nature
Volume
516
Issue
7529
Pages
56-61
Date Published
2014 Dec 04
ISSN
1476-4687
URL
DOI
10.1038/nature13920
PubMed ID
25471879
PubMed Central ID
PMC4256722
Links
Grant list
T32 HL066987 / HL / NHLBI NIH HHS / United States
P50 HG005550 / HG / NHGRI NIH HHS / United States
F32 HD075541 / HD / NICHD NIH HHS / United States
DP1 CA174427 / CA / NCI NIH HHS / United States
R01 GM107536 / GM / NIGMS NIH HHS / United States
P30 HD018655 / HD / NICHD NIH HHS / United States
K01 DK096013 / DK / NIDDK NIH HHS / United States
Howard Hughes Medical Institute / United States
R24 DK092760 / DK / NIDDK NIH HHS / United States
P50 HG006193 / HG / NHGRI NIH HHS / United States
T32 HL007623 / HL / NHLBI NIH HHS / United States
DP1 OD003958 / OD / NIH HHS / United States