RT Journal Article
SR Electronic
T1 The basal level of gene expression associated with chromatin loosening shapes Waddington landscapes and controls cell differentiation
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 738120
DO 10.1101/738120
A1 Gilles Flouriot
A1 Charly Jehanno
A1 Yann le Page
A1 Pascale le Goff
A1 Benjamin Boutin
A1 Denis Michel
YR 2019
UL http://biorxiv.org/content/early/2019/08/16/738120.abstract
AB The baseline level of transcription is variable and seriously complicates the normalization of comparative transcriptomic data, but its biological importance remains unappreciated. We show that this ingredient is in fact crucial for the interpretation of molecular biology results. It 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. A theoretical analysis of gene circuits formally involved in differentiation, 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. Together, these results unveil a generic principle of epigenetic landscape remodeling in which the basal gene expression level, notoriously important in pluripotent cells, allows the maintenance of stemness by generating a specific landscape and in turn, its reduction favors multistability and thereby differentiation. This study highlights how heterochromatin maintenance is essential for preventing pathological cellular reprogramming, age-related diseases and cancer.