Abstract:
As human progenitor cells differentiate into neurons, the activities of many genes change; these changes are maintained within a narrow range, referred to as genome homeostasis. This process, which alters the synchronization of the entire expressed genome, is distorted in neurodevelopmental diseases such as schizophrenia. The coordinated gene activity networks formed by altering sets of genes comprise recurring coordination modules, governed by the entropy-controlling action of nuclear FGFR1, known to be associated with DNA topology. These modules can be modeled as energy-transferring circuits, revealing that genome homeostasis is maintained by reducing oscillations (noise) in gene activity while allowing gene activity changes to be transmitted across networks; this occurs more readily in neuronal committed cells than in neural progenitors. These findings advance a model of an \"entangled\" global genome acting as a flexible, coordinated homeostatic system that responds to developmental signals, is governed by nuclear FGFR1, and is reprogrammed in disease.
摘要:
随着人类祖细胞分化为神经元,许多基因的活动发生变化;这些变化保持在一个狭窄的范围内,称为基因组稳态。这个过程,这改变了整个表达基因组的同步,在精神分裂症等神经发育疾病中被扭曲。通过改变基因集形成的协调基因活动网络包括重复的协调模块,受核FGFR1的熵控制作用支配,已知与DNA拓扑相关。这些模块可以建模为能量转移电路,揭示了通过减少基因活性中的振荡(噪声)来维持基因组稳态,同时允许基因活性变化通过网络传播;这在神经元定向细胞中比在神经祖细胞中更容易发生。这些发现提出了一个“纠缠”全球基因组的模型,响应发育信号的协调稳态系统,由核FGFR1控制,并在疾病中重新编程。