Abstract：
:A number of key regulators of mouse embryonic stem (ES) cell identity, including the transcription factor Nanog, show strong expression fluctuations at the single-cell level. The molecular basis for these fluctuations is unknown. Here we used a genetic complementation strategy to investigate expression changes during transient periods of Nanog downregulation. Employing an integrated approach that includes high-throughput single-cell transcriptional profiling and mathematical modelling, we found that early molecular changes subsequent to Nanog loss are stochastic and reversible. However, analysis also revealed that Nanog loss severely compromises the self-sustaining feedback structure of the ES cell regulatory network. Consequently, these nascent changes soon become consolidated to committed fate decisions in the prolonged absence of Nanog. Consistent with this, we found that exogenous regulation of Nanog-dependent feedback control mechanisms produced a more homogeneous ES cell population. Taken together our results indicate that Nanog-dependent feedback loops have a role in controlling both ES cell fate decisions and population variability.
journal_name
Nat Cell Bioljournal_title
Nature cell biologyauthors
MacArthur BD,Sevilla A,Lenz M,Müller FJ,Schuldt BM,Schuppert AA,Ridden SJ,Stumpf PS,Fidalgo M,Ma'ayan A,Wang J,Lemischka IRdoi
10.1038/ncb2603subject
Has Abstractpub_date
2012-11-01 00:00:00pages
1139-47issue
11eissn
1465-7392issn
1476-4679pii
ncb2603journal_volume
14pub_type
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