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

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The Basal Level of Gene Expression Associated with Chromatin Loosening Shapes Waddington Landscapes and Controls Cell Differentiation.
Journal of Molecular Biology ( IF 4.7 ) Pub Date : 2020-02-24 , DOI: 10.1016/j.jmb.2020.02.016
Gilles Flouriot ₁ , Charly Jehanno ₂ , Yann Le Page ₁ , Pascale Le Goff ₁ , Benjamin Boutin ₃ , Denis Michel ₁

Affiliation

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.

中文翻译：

与染色质松弛形状相关的基因表达的基础水平塑造了Waddington景观并控制了细胞分化。

转录的基线水平是可变的并且难以量化，严重使比较转录组数据的标准化复杂化，但是其生物学重要性仍然未被认识。我们表明，这种目前被忽视的成分对于控制基因网络的多重稳定性并因此控制细胞分化至关重要。基础表达与通过DNA可及性测得的染色质松弛程度相关，并通过转录组特征评估系统性地导致细胞去分化，而与所使用的分子和细胞工具无关。正式参与发育分叉的模型基因网络基序的建模揭示了Waddington的表观遗传景观是通过非特异性表达的水平进行重组的，这样祖细胞和分化细胞的吸引子可以相互排斥。这种机制是通用的，并且不涉及所涉及基因的特殊性质，只要能用自主基础表达正确描述多稳态回路即可。这些结果解释了基因表达噪声，染色质去浓缩和细胞去分化之间早已建立的关系，并强调了异染色质维持对于预防病理性细胞重编程，与年龄有关的疾病和癌症的重要性。

更新日期：2020-02-25

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