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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., Comment: 20 pages, 8 figures

Despite their dynamic nature, certain chromatin marks must be maintained over the long term. This is particulary true for histone 3 lysine 9 (H3K9) trimethylation, that is involved in the maintenance of healthy differentiated cellular states by preventing inappropriate gene expression, and has been recently identified as the most efficient barrier to cellular reprogramming in nuclear transfer experiments. We propose that the capacity of the enzymes SUV39H1/2 to rebind to a minor fraction of their products, either directly or via HP1, contributes to the solidity of this mark through (i) a positive feedback involved in its establishment by the mutual enforcement of H3K9me3 and SUV39H1/2 and then (ii) a negative feedback sufficient to strongly stabilize H3K9me3 heterochromatin in post-mitotic cells by generating local enzyme concentrations capable of counteracting transient bursts of demethylation. This model does not require direct molecular interactions with adjacent nucleosomes and is favoured by a series of additional mechanisms including (i) the protection of chromatin-bound SUV39H1/2 from the turnovers of soluble proteins, which can explain the uncoupling between the cellular contents in SUV39H1 mRNA and protein; (ii) the cooperative dependence on the local density of the H3K9me3 of HP1-dependent heterochomatin condensation and, dispensably (iii) restricted enzyme exchanges with chromocenters confining the reactive bursts of SUV39H1/2 in heterochromatin. This mechanism illustrates how seemingly static epigenetic states can be firmly maintained by dynamic and reversible modifications., Comment: 20 pages, 9 figures

Epigenetics is most often reduced to chromatin marking in the current literature, whereas this notion was initially defined in a more general context. This restricted view ignores that epigenetic memories are in fact more robustly ensured in living systems by steady state mechanisms with permanent molecule renewal. This misconception is likely to result from misleading intuitions and insufficient dialogues between traditional and quantitative biologists. To demystify dynamic epigenetics, its most famous image, a Waddington landscape and its attractors, are explicitly drawn. The simple example provided is sufficient to highlight the main requirements and characteristics of dynamic gene networks, underlying cellular differentiation, de-differentiation and trans-differentiation., Comment: 18 pages, 2 figures