与染色质疏松相关的基因表达的基础水平形成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
摘要：
转录的基线水平是可变的并且难以量化，这使得比较转录组学数据的标准化严重复杂化，但其生物学重要性仍然未被认识到。我们发现，这种目前被忽视的成分是控制基因网络的多稳定性，因此细胞分化所必需的。基础表达与通过DNA可及性测量的染色质松动程度相关，并且系统地导致如通过转录组学特征评估的细胞去分化，而不管使用的分子和细胞工具。建模基因网络模体正式参与发展的分叉，揭示了沃丁顿的表观遗传景观重构的非特异性表达水平，这样的祖细胞和分化细胞的吸引子可以是相互排斥的。这种机制是普遍的，并认为超出了特定性质的基因参与，提供了多稳态电路正确描述与自主基础表达。这些结果解释了基因表达噪音、染色质去浓缩和细胞去分化之间长期建立的关系，并强调了异染色质维持对于预防病理性细胞重编程、年龄相关疾病和癌症至关重要。
英文摘要：
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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