Proper timing of gene expression is central to lymphocyte development and differentiation. Lymphocytes often delay gene activation for hours to days after the onset of signaling components, which act on the order of seconds to minutes. Such delays play a prominent role during the intricate choreography of developmental events and during the execution of an effector response. Though a number of mechanisms are sufficient to explain timing at short timescales, it is not known how timing delays are implemented over long timescales that may span several cell generations. Based on the literature, we propose that a class of cis‐regulatory elements, termed “timing enhancers,” may explain how timing delays are controlled over these long timescales. By considering chromatin as a kinetic barrier to state switching, the timing enhancer model explains experimentally observed dynamics of gene expression where other models fall short. In this review, we elaborate on features of the timing enhancer model and discuss the evidence for its generality throughout development and differentiation. We then discuss potential molecular mechanisms underlying timing enhancer function. Finally, we explore recent evidence drawing connections between timing enhancers and genetic risk for immunopathology. We argue that the timing enhancer model is a useful framework for understanding how cis‐regulatory elements control the central dimension of timing in lymphocyte biology.

中文翻译：

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寻找失去的时间：增强剂作为淋巴细胞发育和分化时间的调节剂


基因表达的正确时机对于淋巴细胞的发育和分化至关重要。淋巴细胞通常会在信号成分出现后延迟基因激活数小时至数天，信号成分的作用时间约为几秒至几分钟。这种延迟在发育事件的复杂编排和效应反应的执行过程中发挥着重要作用。尽管许多机制足以解释短时间尺度上的时序，但尚不清楚如何在可能跨越几代细胞的长时间尺度上实现时序延迟。根据文献，我们提出一类称为“时序增强器”的顺式调节元件，可以解释如何在这些长的时间尺度上控制时序延迟。通过将染色质视为状态转换的动力学障碍，定时增强器模型解释了实验观察到的基因表达动态，而其他模型则无法做到这一点。在这篇综述中，我们详细阐述了时序增强器模型的特征，并讨论了其在整个开发和分化过程中的通用性的证据。然后我们讨论定时增强子功能背后的潜在分子机制。最后，我们探讨了最近的证据，揭示了时间增强剂与免疫病理学遗传风险之间的联系。我们认为，时间增强子模型是理解顺式调控元件如何控制淋巴细胞生物学中时间中心维度的有用框架。