Martinez-Arias Lab
Department of Genetics, University of Cambridge
Tibor Kalmár
PhD student
tk295@cam.ac.ukDepartment of Genetics,
Downing Street, Cambridge
CB2 3EH,England
Telephone: +44 1223 766595
Fax: +44 1223 333992
In the year 2005 we have initiated a project centered on the study of transcriptional noise and its regulation on cell fate decision in mammalian cells. We have chosen mouse embryonic stem and carcinoma ells (ES and EC cells) as a model system. There is evidence that the pluripotency of mouse ES and EC cells is associated with the activity of a network of transcription factors with Nanog, Oct4 and Sox2 (NOS) at the core. Interestingly, none of the NOS genes are specific to ES cells: Oct4 is expressed in the epiblast, in particular epiblast around the streak, early neural ectoderm, and germ cells; Nanog is expressed in proximal posterior epiblast (where the streak will form), forebrain and germ cells, while Sox2 is expressed in the inner cell mass and the epiblast and at the beginning of neurogenesis, Sox2 expression becomes restricted to the neural primordium. These observations indicate that, in the context of pluripotency, the interaction between these factors is likely to be more important for than simply their presence.
Using fluorescent reporters for the expression of Nanog we
observe that a population of ES cells is described by a
dynamic distribution, characterized by two peaks of
fluorescence, one High (HN) and one Low (LN). Typically the LN
state is only 5–20% of the total population, depending on the
culture conditions and cells in this state are more prone to
differentiate.
Modelling of the activity of Nanog reveals that a
simple network between Oct4/Sox2 (A) and Nanog (N) can account for the
distribution and its properties as long as its activity is driven by
transcriptional noise. The model also predicts that the LN state is
unstable something that is born out experimentally.
We also show that Wnt signalling is involved in tuning the level of noise of the network and, specifically, that it modulates the rate of transition between the LN and HN states. We suggest that transcriptional noise might be an essential element of the pluripotent state and that the function of Nanog, Oct4 and Sox2 is to act as a network that promotes and maintains transcriptional noise to interfere with the differentiation signals. Similar observations have been made recently in mammalian progenitor cells and together these results suggest that distributions of gene expression over populations might contain information about cell fates and the probabilities of cell fate transitions.