In search of lost time: Enhancers as modulators of timing in lymphocyte development and differentiation.
In search of lost time: Enhancers as modulators of timing in lymphocyte development and differentiation.
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DOI：
10.1111/imr.12946
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发表时间：
2021-03
影响因子：
8.7
通讯作者：
Kueh HY
中科院分区：
文献类型：
--
作者：
Chu JM;Pease NA;Kueh HY
适当的基因表达时机对淋巴细胞的发育和分化至关重要。淋巴细胞通常在信号成分出现后延迟数小时到数天的基因激活，这些信号成分的作用在几秒钟到几分钟的数量级。这种延迟在复杂的发育时间编排和效应器反应的执行过程中发挥着突出的作用。虽然许多机制足以解释短时间尺度上的计时，但还不知道如何在可能跨越几代细胞的长时间尺度上实现计时延迟。在文献的基础上，我们提出了一类被称为“定时增强器”的顺式调控元件，可以解释这些长时间尺度上的定时延迟是如何被控制的。通过将染色质视为状态转换的动力学障碍，计时增强器模型解释了实验观察到的基因表达动力学，而其他模型则做不到这一点。在这篇综述中，我们详细阐述了计时增强子模型的特点，并讨论了其在发育和分化过程中具有普遍性的证据。然后，我们讨论了潜在的分子机制潜在的定时增强子功能。最后，我们探索了最近的证据，得出了计时增强剂和免疫病理学遗传风险之间的联系。我们认为，计时增强器模型是一个有用的透镜，通过它可以理解顺式调节元件如何控制淋巴细胞生物学中时间的中心维度。
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 timing 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”, can 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 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 lens through which to understand how cis-regulatory elements control the central dimension of time in lymphocyte biology.
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DOI：
10.15252/embj.201592534
发表时间：
2016-03-01
期刊：
The EMBO journal
影响因子：
--
作者：
Bevington SL;Cauchy P;Piper J;Bertrand E;Lalli N;Jarvis RC;Gilding LN;Ott S;Bonifer C;Cockerill PN
通讯作者：
Cockerill PN
DOI：
10.1038/nrm4043
发表时间：
2015-09
期刊：
Nature reviews. Molecular cell biology
影响因子：
--
作者：
Du J;Johnson LM;Jacobsen SE;Patel DJ
通讯作者：
Patel DJ
在单细胞水平上表观遗传调节的动力学。
DOI：
10.1126/science.aab2956
发表时间：
2016-02-12
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Bintu L;Yong J;Antebi YE;McCue K;Kazuki Y;Uno N;Oshimura M;Elowitz MB
通讯作者：
Elowitz MB
影响因子：
48
作者：
Diao Y;Fang R;Li B;Meng Z;Yu J;Qiu Y;Lin KC;Huang H;Liu T;Marina RJ;Jung I;Shen Y;Guan KL;Ren B
通讯作者：
Ren B
影响因子：
16
作者：
Cirillo, LA;Zaret, KS
通讯作者：
Zaret, KS