节律性转录因子驱动哺乳动物昼夜节律生物钟

生物体通过内在的昼夜节律生物钟调整生理行为和代谢生化反应来适应昼夜环境周期性变化。哺乳动物的昼夜节律生物钟核心连锁环通过驱动特异性的转录因子来维持整个基因组转录的节律性。生物钟与代谢的内稳态密切相关,生物钟的紊乱会引起各种疾病,该领域的研究能够促进时间疗法的发展来维持生命的健康,甚至可以延缓衰老。     

RNA甲基化依赖的RNA加工调控昼夜节律生物钟的速度

<正>哺乳动物的昼夜节律生物钟主要通过调控代谢开关或限速酶的表达来调节新陈代谢。真核生物的生物钟包括一个转录-翻译负反馈调节通路,通过这个通路,生物钟基因调节它们自身以及重要代谢基因的表达。多年前人们就已知道肝脏中大约10%的基因具有昼夜节律性,而近些年的RNA测序研究表明,在这些节律性的基因中,仅有大约五分之一是由从头转录所驱使的。这一发现提示对RNA剪接和加工的调控具有非常重要的生物学意义。     

哺乳动物昼夜节律机制研究进展

地球以24 h为自转周期,为此,生活在地球上的不同生物也通过自身约24 h的内在节律的形成来适应昼夜环境的变化,这一系统即为生物钟。在哺乳类动物中,生物钟主要通过涵盖转录与翻译水平的核心连锁环驱动特异性的转录因子来维持整个基因组转录的昼夜节律性,从而使得不同组织与器官的生理功能能够适应环境剧烈的昼夜变化。现将在综述哺乳类动物昼夜节律形成机制及其生理功能研究进展的基础上,对今后的研究方向作出展望。     

哺乳动物昼夜节律生物钟研究进展

昼夜节律生物钟是一种以近似24小时为周期的自主维持的振荡器,在分子水平上,该振荡器是一个由9个基因组成的转录翻译反馈环路系统。它能受外界环境影响重新设置节律,使自身机体活动处于最佳状态。除了进行自我调节外,生物钟基因还能通过调节代谢途径中特定基因表达而影响机体生理生化过程。在过去的几年里,借用遗传学和分子生物学工具,我们对哺乳动物昼夜节律生物钟的分子基础有了新的认识,本文综述了这一进展,并展望了它们在研究人的昼夜节律行为异常领域的前景。     

O-GlcNAc修饰调节生物节律研究进展

生物体的睡眠/觉醒、进食等行为以及各种生理、生化、代谢过程都遵循着大约24 h的周期性变化,称为昼夜节律(circadian rhythms)。昼夜节律与能量代谢之间存在着紧密的联系。位于下丘脑视交叉上核(suprachiasmatic nuclei,SCN)的中枢生物钟与外周组织细胞中的生物钟共同组成了哺乳动物的昼夜节律系统。以CLOCK/BMAL1异二聚体为核心的转录/翻译负反馈环保障了节律系统的正常运行。各种蛋白质翻译后修饰参与了昼夜节律的调控。综述了氧连β-N-乙酰葡糖胺修饰(O-Glc NAcylation)在调节昼夜节律中发挥的重要作用。O-Glc NAc修饰可以增强一些生物钟蛋白的稳定性及转录活性,也可以影响其他一些生物钟蛋白的磷酸化及细胞定位。抑制生物钟蛋白的O-Glc NAc修饰导致细胞节律衰弱和多种节律基因表达下调。研究表明,O-Glc NAc作为机体能量代谢的感受器参与了多条细胞代谢相关信号转导通路的调节,O-Glc NAc修饰为能量代谢影响昼夜节律提供了一条新的途径。     

生物钟节律与肝脏代谢稳态

生物钟(circadian clock)是机体内在的自主性计时系统,包括视交叉上核(suprachiasmatic nucleus, SCN)中枢生物钟与各组织外周生物钟。分子生物钟的核心机制包括CLOCK/BMAL1二聚体诱导抑制因子CRYs和PERs的转录,CRYs/PERs复合物反馈抑制前者转录活性,进而使这些生物钟核心因子以及节律输出基因的转录水平呈24 h振荡的反馈调节核心环路,以及REV-ERBα和RORα调控BMAL1转录的补充环路。机体大约80%的蛋白编码基因表达呈现明显的昼夜节律性特征,生物钟系统使生物能够适应地球自转所产生的昼夜节律(近日节律),使机体的代谢平衡与能量相互协同。生物钟与代谢稳态相互依存、互为基础,使机体能够高效利用能量,协同机体不同组织,快速适应内外环境变化。肝脏作为机体代谢的中枢器官,其进行的各种生理活动几乎都受到生物钟的控制。生物钟与肝脏代谢调控之间存在多重交互调控机制,两者的交互平衡失调是代谢性疾病的高风险因素。本文主要就肝脏的糖、脂和蛋白质代谢的节律性调控进行了综述,并强调了线粒体功能的振荡,讨论了肝脏代谢对生物钟的反馈调节,并对生物钟研究方法和应用进行展望。     

果蝇昼夜节律生物钟机制研究进展

昼夜节律生物钟包括输入途径、生物钟本身和输出途径。果蝇作为昼夜节律生物钟研究的前沿模式生物需被进一步了解。本文对果蝇昼夜节律生物钟的钟基因、激酶和磷酸酶的调控、两个相互依赖的转录/翻译反馈环路、生物钟细胞和昼夜节律行为进行了综述。     

生物钟基因介导卵巢功能调控的分子机制研究

地球的自转产生了以24 h为周期的昼夜节律,因此生物的生理过程和行为活动大都呈现一个近似24 h的周期节律改变,以适应环境的不断变化。昼夜节律在整体水平是一个系统性的调控,它的产生、维持和调控依赖于细胞内生物钟基因的震荡型转录翻译负反馈环路。研究表明,生物钟在卵巢动情周期和生殖系统发育过程中发挥重要作用。本篇综述主要阐述了自卵巢生物钟发现后的种种研究成果,包括卵巢生物钟对类固醇激素生成及排卵的影响,生物钟基因对生育能力的影响,以及生物钟调控与女性生殖系统疾病的相关性。     

果蝇昼夜节律的调控机制

40多年前的遗传筛选鉴定了第一个果蝇生物钟基因period,开启了果蝇生物钟调控机制的研究。随着更多生物钟基因被发现,一个由转录水平的调控及转录后水平的修饰组成的负反馈环路模型逐步形成,被认为是调控昼夜节律的核心分子机制。生物钟驱动果蝇脑内约150个神经元的活动,这些神经元在不同的环境条件下通过不同的方式互作,共同调控果蝇的行为节律。昼夜环境变化中最显著的是明暗变化。蓝光受体cryptochrome在光对昼夜节律的调控中起重要作用。     

昼夜节律钟调控代谢的研究进展

生理和行为的昼夜节律性调控对健康生活是必需的。越来越多的流行病学和遗传学证据显示昼夜节律的破坏与代谢紊乱性疾病相关联。在分子水平上,昼夜节律受到时钟蛋白组成的转录一翻译负反馈环的调控。时钟蛋白通过以下两种途径调节代谢：首先,时钟蛋白作为转录因子直接调节一些代谢关键步骤的限速酶和代谢相关核受体的表达,其次作为代谢相关核受体的辅调节因子来激活或抑制其转录活性。虽然时钟蛋白对代谢途径的调节导致代谢物水平呈昼夜节律振荡,但是产生的代谢物反过来又可以影响昼夜节律钟基因的表达,进而影响昼夜节律钟。深入研究昼夜节律钟与代谢的交互调节可能为治疗某些代谢紊乱性疾病提供新的治疗方案。     

Comparative analysis of teleost fish genomes reveals preservation of different ancient clock duplicates in different fishes

Clock (Circadian locomotor output cycle kaput) was the first vertebrate circadian clock gene identified in a mouse forward genetics mutagenesis screen. It encodes a bHLH-PAS protein that is highly conserved throughout evolution. Tetrapods also have the second Clock gene, Clock2 or Npas2 (Neuronal PAS domain protein 2). Conversely, the fruit fly, an invertebrate, has only one clock gene. Interrogation of the five teleost fish genome databases revealed that the zebrafish and the Japanese pufferfish (fugu) each have three clock genes, whereas the green spotted pufferfish (tetraodon), the Japanese medaka fish and the three-spine stickleback each have two clock genes. Phylogenetic and splice site analyses indicated that zebrafish and fugu each have two clock1 genes, clock1a and clock1b and one clock2; tetraodon also have clock1a and clock1b but do not have clock2; and medaka and stickleback each have clock1b and one clock2. Genome neighborhood analysis further showed that clock1a/clock1b in zebrafish, fugu and tetraodon is an ancient duplicate. While the dN/dS ratios of these three fish clock duplicates are all <1, indicating that purifying selection has acted upon them; the Tajima relative rate test showed that all three fish clock duplicates have asymmetric evolutionary rates, implicating that one of these duplicates have been under positive selection or relaxed functional constraint. These results support the view that teleost fish clock genes were generated from an ancient genome-wide duplication, and differential gene loss after the duplication resulted in retention of different ancient duplicates in different teleost fishes, which could have contributed to the evolution of the distinct fish circadian clock mechanisms.     

Analysis of the molecular pathophysiology of sleep disorders relevant to a disturbed biological clock

Genetic studies have revealed several clock gene variations/mutations involved in the manifestation of sleep disorders or interindividual differences in sleep–wake patterns, but only part of the genetic risk can be explained by the gene variations/mutations identified to date. Recent progress in research into circadian rhythm generation has provided efficient tools for eliciting the molecular basis of clock-relevant sleep disorders, complementing traditional genetic analysis. While the human master clock resides in the suprachiasmatic nucleus of the hypothalamus (central clock), peripheral tissue cells also generate self-sustained circadian oscillations of clock gene expression (peripheral clock), enabling estimation of individual human clock properties through a single collection of skin fibroblasts or venous blood cells. Some of the established cell lines exhibit autonomous circadian oscillations of clock gene expression, and introduction of clock gene variations into these cell lines by gene targeting makes it possible to investigate changes in the circadian phenotype induced by these variations/mutations without the need for generating transgenic animals. Estimation of human clock properties using peripheral tissue cells, in addition to genetic analysis, will facilitate comprehensive explication of the genetic risk of a variety of disorders relevant to biological clock disturbances, including sleep disorders, mood disorders, and metabolic diseases.     

A survey of genomic studies supports association of circadian clock genes with bipolar disorder spectrum illnesses and lithium response

Circadian rhythm abnormalities in bipolar disorder (BD) have led to a search for genetic abnormalities in circadian "clock genes" associated with BD. However, no significant clock gene findings have emerged from genome-wide association studies (GWAS). At least three factors could account for this discrepancy: complex traits are polygenic, the organization of the clock is more complex than previously recognized, and/or genetic risk for BD may be shared across multiple illnesses. To investigate these issues, we considered the clock gene network at three levels: essential "core" clock genes, upstream circadian clock modulators, and downstream clock controlled genes. Using relaxed thresholds for GWAS statistical significance, we determined the rates of clock vs. control genetic associations with BD, and four additional illnesses that share clinical features and/or genetic risk with BD (major depression, schizophrenia, attention deficit/hyperactivity). Then we compared the results to a set of lithium-responsive genes. Associations with BD-spectrum illnesses and lithium-responsiveness were both enriched among core clock genes but not among upstream clock modulators. Associations with BD-spectrum illnesses and lithium-responsiveness were also enriched among pervasively rhythmic clock-controlled genes but not among genes that were less pervasively rhythmic or non-rhythmic. Our analysis reveals previously unrecognized associations between clock genes and BD-spectrum illnesses, partly reconciling previously discordant results from past GWAS and candidate gene studies.     

松果体昼夜节律生物钟分子机制的研究进展

在各种非哺乳类脊椎动物中 ,松果体起着中枢昼夜节律振荡器的作用。近来 ,在鸟类松果体中相继发现了几种钟基因 ,如Per、Cry、Clock和Bmal等 ,其表达的时间变化规律与哺乳类视交叉上核 (SCN)的非常相似。钟的振荡由其自身调控反馈环路的转录和翻译组成 ,鸟类松果体和哺乳类SCN似乎具有共同的钟振荡基本分子构架 ;若干钟基因产物作为正向或负向调节子影响钟的振荡 ;昼夜性的控时机制同时也需要翻译后事件的参与。这些过程对钟振荡器的稳定性和 /或钟导引的光输入通路有着重要的调控作用     

Osmotic stress at the barley root affects expression of circadian clock genes in the shoot

The circadian clock is an important timing system that controls physiological responses to abiotic stresses in plants. However, there is little information on the effects of the clock on stress adaptation in important crops, like barley. In addition, we do not know how osmotic stress perceived at the roots affect the shoot circadian clock. Barley genotypes, carrying natural variation at the photoperiod response and clock genes Ppd‐H1 and HvELF3, were grown under control and osmotic stress conditions to record changes in the diurnal expression of clock and stress‐response genes and in physiological traits. Variation at HvELF3 affected the expression phase and shape of clock and stress‐response genes, while variation at Ppd‐H1 only affected the expression levels of stress genes. Osmotic stress up‐regulated expression of clock and stress‐response genes and advanced their expression peaks. Clock genes controlled the expression of stress‐response genes, but had minor effects on gas exchange and leaf transpiration. This study demonstrated that osmotic stress at the barley root altered clock gene expression in the shoot and acted as a spatial input signal into the clock. Unlike in Arabidopsis, barley primary assimilation was less controlled by the clock and more responsive to environmental perturbations, such as osmotic stress.