Systems Level Understanding of Circadian Integration with Cell Physiology.
Systems Level Understanding of Circadian Integration with Cell Physiology.
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DOI：
10.1016/j.jmb.2020.02.002
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发表时间：
2020-05-29
影响因子：
5.6
通讯作者：
Liu AC
中科院分区：
文献类型：
--
作者：
Morris AR;Stanton DL;Roman D;Liu AC
哺乳动物的生物钟调节着各种各样的生理和行为过程。反过来，它的破坏与睡眠不足，代谢综合征，神经和精神疾病以及癌症有关。在世纪之交，生物钟被确定是由十几个核心时钟基因组成的转录负反馈机制调控的。最近，大规模的基因组研究已经将时钟扩展为一个由数千个基因输出和输入组成的复杂网络。昼夜节律研究的一个主要任务是利用系统生物学方法揭示细胞振荡行为的基本原理，并在基因组水平上以时空分辨率推进对生物功能的理解。这篇综述着重于为生物钟提供输入的基因和途径。几个新出现的例子包括AMP活化蛋白激酶AMPK、营养/能量传感器mTOR、NAD+依赖性脱乙酰酶SIRT 1、缺氧诱导因子HIF 1 α、氧化应激诱导因子NRF 2和促炎因子NF-κB。在其他继续被揭示的途径中，这些输入途径反映了时钟和细胞生理学之间通过核心时钟基因和蛋白质的调节的广泛相互作用。虽然这种串扰的范围是公认的，但精确的分子连接是稀缺的，并且底层的调控机制还没有很好地理解。未来的研究必须利用遗传和基因组工具和技术，网络分析和计算建模来表征其他修饰剂和输入途径。这种基于系统的框架有望促进对昼夜节律计时系统的理解，并可能通过相关的输入途径增强昼夜节律功能。
The mammalian circadian clock regulates a wide variety of physiological and behavioral processes. In turn, its disruption is associated with sleep deficiency, metabolic syndrome, neurological and psychiatric disorders, and cancer. At the turn of the century, the circadian clock was determined to be regulated by a transcriptional negative feedback mechanism composed of a dozen core clock genes. More recently, large-scale genomic studies have expanded the clock into a complex network composed of thousands of gene outputs and inputs. A major task of circadian research is to utilize systems biological approaches to uncover the governing principles underlying cellular oscillatory behavior and advance understanding of biological functions at the genomic level with spatiotemporal resolution. This review focuses on the genes and pathways that provide inputs to the circadian clock. Several emerging examples include AMP-activated protein kinase AMPK, nutrient/energy sensor mTOR, NAD+-dependent deacetylase SIRT1, hypoxia-inducible factor HIF1α, oxidative stress-inducible factor NRF2, and the proinflammatory factor NF-κB. Among others that continue to be revealed, these input pathways reflect the extensive interplay between the clock and cell physiology through the regulation of core clock genes and proteins. While the scope of this crosstalk is well-recognized, precise molecular links are scarce, and the underlying regulatory mechanisms are not well understood. Future research must leverage genetic and genomic tools and technologies, network analysis, and computational modeling to characterize additional modifiers and input pathways. This systems-based framework promises to advance understanding of the circadian timekeeping system and may enable the enhancement of circadian functions through related input pathways.
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DOI：
10.1146/annurev-pharmtox-010617-052645
发表时间：
2018-01-06
影响因子：
12.5
作者：
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影响因子：
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DOI：
10.1073/pnas.1619320114
发表时间：
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影响因子：
11.1
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DOI：
10.1073/pnas.1612917113
发表时间：
2016-10-11
影响因子：
11.1
作者：
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影响因子：
64.5
作者：
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