  The baseline level of transcription, which is variable and difficult to
quantify, seriously complicates the normalization of comparative transcriptomic
data, but its biological importance remains unappreciated. We show that this
currently neglected ingredient is essential for controlling gene network
multistability and therefore cellular differentiation. Basal expression is
correlated to the degree of chromatin loosening measured by DNA accessibility,
and systematically leads to cellular dedifferentiation as assessed by
transcriptomic signatures, irrespective of the molecular and cellular tools
used. Modeling gene network motifs formally involved in developmental
bifurcations, reveals that the epigenetic landscapes of Waddington are
restructured by the level of non specific expression, such that the attractors
of progenitor and differentiated cells can be mutually exclusive. This
mechanism is universal and holds beyond the particular nature of the genes
involved, provided the multistable circuits are correctly described with
autonomous basal expression. These results explain the relationships long
established between gene expression noise, chromatin decondensation and
cellular dedifferentiation, and highlight how heterochromatin maintenance is
essential for preventing pathological cellular reprogramming, age-related
diseases and cancer.
