论文标题

与染色质松动形状相关的基因表达的基础水平waddington景观并控制细胞分化

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

论文作者

Flouriot, Gilles, Jehanno, Charly, Page, Yann Le, Goff, Pascale Le, Boutin, Benjamin, Michel, Denis

论文摘要

可变且难以量化的转录水平严重使比较转录组数据的归一化变得复杂,但其生物学重要性仍然没有批准。我们表明,这种当前被忽略的成分对于控制基因网络的多稳定性和细胞分化至关重要。基础表达与通过DNA可及性测量的染色质松动的程度相关,并系统地导致细胞去分化,如转录组特征所评估,而与使用的分子和细胞工具无关。建模基因网络基序正式参与发育分叉,表明沃丁顿的表观遗传景观被非特定表达的水平进行了重组,因此祖细胞和分化细胞的吸引子可以互斥。这种机制是通用的,并且超出了所涉及的基因的特殊性质,前提是用自主基底表达正确描述了多稳态的电路。这些结果解释了基因表达噪声,染色质降解和细胞去分化之间的长期关系,并突出了异染色质维持对于预防病理细胞重编程,与年龄相关的疾病和癌症至关重要。

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.

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