Modeling the interactions of sense and antisense Period transcripts in the mammalian circadian clock network.
Modeling the interactions of sense and antisense Period transcripts in the mammalian circadian clock network.
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DOI：
10.1371/journal.pcbi.1005957
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发表时间：
2018-03
影响因子：
4.3
通讯作者：
Tyson JJ
中科院分区：
文献类型：
--
作者：
Battogtokh D;Kojima S;Tyson JJ
近年来，反义转录在基因表达调控中的重要作用越来越明显。生物钟也不例外：哺乳动物核心时钟基因PERIOD 2（PER 2）的反义转录物，我们将其称为Per 2AS RNA，以昼夜节律周期振荡，并从Per 2 mRNA的峰值表达发生近12小时的相移。在本文中，我们问Per 2AS是否在哺乳动物的生物钟中起着调节作用，通过计算机研究Per 2和Per 2AS RNA之间的相互作用对昼夜节律的潜在影响。基于反相表达模式，我们考虑两个假设Per 2和Per 2AS如何相互干扰彼此的表达。在我们的转录前模型中，Per 2AS RNA从非编码链的转录抑制Per 2 mRNA从编码链的转录，反之亦然。在我们的转录后模型中，Per 2和Per 2AS转录物形成双链RNA双链体，并迅速降解。为了研究这两种可能的机制，我们在哺乳动物生物钟的分子调控网络的数学模型中添加了描述我们的替代假设的术语。我们的转录前模型预测，Per 2和Per 2AS之间的转录干扰可以产生替代模式的昼夜节律振荡，我们的特征在于核心时钟基因的振荡幅度和相位。在我们的转录后模型中，Per 2/Per 2AS双链体的形成抑制了昼夜节律。在结合转录前和转录后控制的模型中，昼夜节律蛋白的周期、振幅和相位对Per 2AS的表达速率表现出非单调依赖性。所有这三种模型都为观察到的Per 2和Per 2AS RNA的反相、昼夜节律振荡提供了潜在的解释。他们做出了不一致的预测，这些预测可以通过实验来检验，以区分这些替代假设。更好地理解生理节律的分子机制无疑将改善与生理节律紊乱相关的人类健康问题的治疗。然而，生物钟中的基因和遗传相互作用的清单仍然不完整。重要的球员可能还不为人知或被低估。例如，在小鼠肝脏中，核心时钟基因PER 2被转录成Per 2 mRNA分子（"正义“转录物）和反义RNA转录物（Per 2AS）。因为重要的是要知道Per 2和Per 2AS之间的相互作用可能会影响昼夜节律基因的表达，我们已经进行了数学建模研究这些相互作用的两种可能的机制。在转录前模型中，Per 2 mRNA干扰Per 2AS RNA的转录，反之亦然。在转录后模型中，Per 2和Per 2AS分子形成双链RNA双链体，其被RNA酶快速降解。我们发现，转录前模型给出了一个更强大的帐户的昼夜节律，反相振荡的Per 2和Per 2AS转录在小鼠肝脏。该模型做出了一个意想不到的预测，即ROR基因和Per 2AS序列的共过表达可以产生一种新的昼夜节律振荡模式，这种模式在当代昼夜节律模型中看不到，也没有在实验中寻找。
In recent years, it has become increasingly apparent that antisense transcription plays an important role in the regulation of gene expression. The circadian clock is no exception: an antisense transcript of the mammalian core-clock gene PERIOD2 (PER2), which we shall refer to as Per2AS RNA, oscillates with a circadian period and a nearly 12 h phase shift from the peak expression of Per2 mRNA. In this paper, we ask whether Per2AS plays a regulatory role in the mammalian circadian clock by studying in silico the potential effects of interactions between Per2 and Per2AS RNAs on circadian rhythms. Based on the antiphasic expression pattern, we consider two hypotheses about how Per2 and Per2AS mutually interfere with each other's expression. In our pre-transcriptional model, the transcription of Per2AS RNA from the non-coding strand represses the transcription of Per2 mRNA from the coding strand and vice versa. In our post-transcriptional model, Per2 and Per2AS transcripts form a double-stranded RNA duplex, which is rapidly degraded. To study these two possible mechanisms, we have added terms describing our alternative hypotheses to a published mathematical model of the molecular regulatory network of the mammalian circadian clock. Our pre-transcriptional model predicts that transcriptional interference between Per2 and Per2AS can generate alternative modes of circadian oscillations, which we characterize in terms of the amplitude and phase of oscillation of core clock genes. In our post-transcriptional model, Per2/Per2AS duplex formation dampens the circadian rhythm. In a model that combines pre- and post-transcriptional controls, the period, amplitude and phase of circadian proteins exhibit non-monotonic dependencies on the rate of expression of Per2AS. All three models provide potential explanations of the observed antiphasic, circadian oscillations of Per2 and Per2AS RNAs. They make discordant predictions that can be tested experimentally in order to distinguish among these alternative hypotheses. A better understanding of the molecular mechanisms underlying circadian rhythms will undoubtedly improve the treatment of human health problems related to circadian dysrhythmias. However, the inventory of genes and genetic interactions in the circadian clock is still incomplete. Important players may yet be unknown or under-appreciated. For example, in mouse liver, the core clock gene PER2 is transcribed into both a Per2 mRNA molecule (a ‘sense’ transcript) and an antisense RNA transcript (Per2AS). Because it is important to know how interactions between Per2 and Per2AS may affect circadian gene expression, we have carried out a mathematical modeling study of two possible mechanisms for these interactions. In the pre-transcriptional model, Per2 mRNA interferes with the transcription of Per2AS RNA and vice versa. In the post-transcriptional model, Per2 and Per2AS molecules form double-stranded RNA duplexes, which are rapidly degraded by RNases. We find that the pre-transcriptional model gives a more robust account of the circadian, antiphasic oscillations of Per2 and Per2AS transcripts in mouse liver. The model makes an unexpected prediction that co-overexpression of the ROR gene and Per2AS sequences can generate a new mode of circadian oscillations not seen in contemporary models of circadian rhythms and not yet looked for experimentally.
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影响因子：
4.3
作者：
Pett JP;Korenčič A;Wesener F;Kramer A;Herzel H
通讯作者：
Herzel H
调整哺乳动物昼夜节律的时钟：两个循环的强大协同作用。
影响因子：
4.3
作者：
Relógio A;Westermark PO;Wallach T;Schellenberg K;Kramer A;Herzel H
通讯作者：
Herzel H
DOI：
10.1073/pnas.0600927103
发表时间：
2006-05-02
影响因子：
11.1
作者：
Dühring, U;Axmann, IM;Wilde, A
通讯作者：
Wilde, A
DOI：
10.1073/pnas.262658899
发表时间：
2002-12-24
影响因子：
11.1
作者：
Battogtokh, D;Asch, DK;Schüttler, HB
通讯作者：
Schüttler, HB
DOI：
10.1073/pnas.0904837106
发表时间：
2009-07-07
影响因子：
11.1
作者：
Mirsky, Henry P.;Liu, Andrew C.;Doyle, Francis J., III
通讯作者：
Doyle, Francis J., III