The Basal Level of Gene Expression Associated with Chromatin Loosening Shapes Waddington Landscapes and Controls Cell Differentiation.

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 nonspecific 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.

The accuracy of biochemical interactions is ensured by endothermic stepwise kinetics.

The discerning behavior of living systems relies on accurate interactions selected from the lot of molecular collisions occurring in the cell. To ensure the reliability of interactions, binding partners are classically envisioned as finely preadapted molecules, selected on the basis of their affinity in one-step associations. But the counterselection of inappropriate interactions can in fact be much more efficiently obtained through difficult multi-step adjustment, whose final high energy state is locked by a fluctuation ratchet. The progressive addition of molecular bonds during stereo-adjustment can be modeled as a predominantly backward random walk whose first arrival is frozen by a micro-irreversible transition. A new criterion of ligand specificity is presented, that is based on the ratio rejection/incorporation. In addition to its role in the selectivity of interactions, this generic recipe can underlie other important biological phenomena such as the regular synthesis at low level of supramolecular complexes, monostable kinetic bimodality, substrate concentration thresholds or the preparation of rapidly depolymerizable structures with stored energy, like microtubules.