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The basal level of gene expression associated with chromatin loosening shapes Waddington landscapes and controls cell differentiation

Gilles Flouriot, Charly Jehanno, Yann le Page, Pascale le Goff, Benjamin Boutin, View ORCID ProfileDenis Michel
doi: https://doi.org/10.1101/738120
Gilles Flouriot
Univ Rennes, Inserm, EHESP, Irset UMR 1085, Rennes, France
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Charly Jehanno
University of Basel, Department of Biomedicin, Basel, Switzerland
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Yann le Page
Univ Rennes, Inserm, EHESP, Irset UMR 1085, Rennes, France
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Pascale le Goff
Univ Rennes, Inserm, EHESP, Irset UMR 1085, Rennes, France
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Benjamin Boutin
Univ Rennes, Institut de Recherches Mathématiques de Rennes, France
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Denis Michel
Univ Rennes, Inserm, EHESP, Irset UMR 1085, Rennes, France
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  • ORCID record for Denis Michel
  • For correspondence: denis.michel@live.fr
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Abstract

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.

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Posted August 16, 2019.
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The basal level of gene expression associated with chromatin loosening shapes Waddington landscapes and controls cell differentiation
Gilles Flouriot, Charly Jehanno, Yann le Page, Pascale le Goff, Benjamin Boutin, Denis Michel
bioRxiv 738120; doi: https://doi.org/10.1101/738120
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The basal level of gene expression associated with chromatin loosening shapes Waddington landscapes and controls cell differentiation
Gilles Flouriot, Charly Jehanno, Yann le Page, Pascale le Goff, Benjamin Boutin, Denis Michel
bioRxiv 738120; doi: https://doi.org/10.1101/738120

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