Department of Bioengineering, University of Washington, Seattle, WA, USA.
Molecular and Cellular Biology Program, University of Washington, Seattle, WA, USA.
Immunol Rev. 2021 Mar;300(1):134-151. doi: 10.1111/imr.12946. Epub 2021 Mar 18.
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.
基因表达的适时性是淋巴细胞发育和分化的核心。淋巴细胞通常在信号成分开始作用后的数小时至数天内延迟基因激活，而信号成分的作用时间在数秒至数分钟之间。这种延迟在发育事件的复杂编排过程中和效应器反应的执行过程中起着重要作用。虽然有许多机制足以解释短时间尺度上的定时，但尚不清楚如何在可能跨越多个细胞世代的长时间尺度上实现定时延迟。基于文献，我们提出了一类顺式调控元件，称为“定时增强子”，可解释定时延迟如何在这些长时间尺度上得到控制。通过将染色质视为状态转换的动力学障碍，定时增强子模型解释了实验观察到的基因表达动力学，而其他模型则无法解释。在这篇综述中，我们详细阐述了定时增强子模型的特征，并讨论了其在整个发育和分化过程中的普遍性证据。然后，我们讨论了定时增强子功能的潜在分子机制。最后，我们探讨了最近的证据，这些证据将定时增强子与免疫病理学的遗传风险联系起来。我们认为，定时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定时这一核心维度的有用框架。
