TRIM22

导语：地球围绕太阳的自转和公转创造了昼夜和季节，适应了这一环境的生物才能够在地球上生存。人类已进化出对日常节律性的适应。但是，人类许多病理包括复杂的心血管和精神疾病均表现出强烈的季节性，这在许多传染病中尤为突出。这些生理变化均与基因组的季节性和昼夜性表达相关，尤其是免疫系统基因。在大家的印象中，太阳系的大体结构是平面化的，八大行星围绕着太阳进行公转。虽然，太阳系中的八大行星运行轨道和太阳是在同一个平面（黄道平面），但是，地球所在的太阳系每时每刻都在运动。太阳带着八颗行星围绕银河系中的黑洞旋转，地球带着月球围绕太阳公转。由此，人类的直观体验便是昼夜和季节。图1 从黄道平面看太阳系运行图（图源：[1]）图2 太阳系真实运行轨迹，太阳带着八颗行星往前飞（图源：[1]）图3 以黄道平面为参照物看到的太阳系运行图（图源：[1]）地球上的动物在不同季节表现出一系列行为和生理适应，例如极地动物的冬眠和毛色改变；哺乳动物的季节性繁殖、生长、食物摄入和迁徙行为。人类许多病理包括复杂的心血管和精神疾病均表现出强烈的季节性，这都要从基因中寻找答案，但关于昼夜/季节节律的全基因组研究却很少。2月6日，PLOS Biology发布了西班牙庞培法布拉大学基因组调控中心研究团队提供的第一个关于人类组织的转录组如何适应主要循环环境条件的综合图谱。该研究通过测量不同类型组织的细胞内基因活动的变化，详细介绍了昼夜节律和循环周期如何在分子水平上影响人类。研究团队利用GTEx联盟产生的跨人类组织的深度转录组数据（来自46个组织的932个死亡人类捐赠者的16151个RNA-seq样本）来研究昼夜节律和循环节律在前所未有的组织数量中的转录影响；GTEx的转录测量完全是在捐赠者死亡时进行的，因此，每个人只有一个时间点的测量数据；此外，GTEx元数据只包括一天的时间和死亡的季节，但不包括死亡的实际日期、星期、甚至月份。这使研究人员人为地将昼夜变化和循环变化区分为日夜变化和季节性变化；当聚集在许多个体上时，这些沿时间随机分布的“转录快照”创造了重现昼夜和季节性转录变化的时间轨迹，因此，它们构成了研究这种变化的独特资源。图4 GTEx样本的昼夜和季节分类（图源：[2]）结果发现：01睾丸受季节影响最大，胸腔中组织受昼夜影响大 除了睾丸，大多数组织在基因表达的季节特异性变化中没有表现出任何偏差，睾丸在秋季显示基因表达大量增加，在春季减少。这一发现可能反映了性腺功能的季节性变化。昼夜和季节变化在很大程度上是不相关的。脑和性腺组织表现出最高的季节性，而胸腔中的组织表现出更强的昼夜调节。这表明基因和组织均受到昼夜和季节变化的不同影响。昼夜变化在肝、肺、心脏和上消化道更为突出，反映了胸腔器官参与昼夜节律过程；而季节性变化对脑子区域和睾丸的影响最强，反映了脑-性腺激素轴在调节对季节性变化的生理反应中的作用。具体而言，胸腔组织的昼夜基因数量最多，包括肺（组织中表达的所有基因的17.2%）、心脏左心室（19.2%）和全血（19%），这可以解释昼夜心率和呼吸模式的差异；相比之下，唾液腺（0.63%）、横结肠（0.67%）、睾丸（0.66%）和大脑（0.86%-7.8%）较少；胃是白天偏好最强的组织，而未暴露在阳光下的皮肤是夜间偏好最强的组织。相比之下，暴露在阳光下的皮肤表现出昼夜偏好，表明紫外线在基因表达的激活中发挥作用。图5 人体组织中昼夜基因总数分类（图源：[2]）02发现新的受昼夜影响的基因 研究人员创建了一个包含445个基因的列表，这些基因在多个组织中具有一致的昼夜模式。该列表包括已知在昼夜节律中发挥重要作用并控制人类何时清醒和活跃的“时钟基因”。时钟基因的表达变异在狒狒和小鼠中是保守的，但是夜行动物老鼠的时钟是倒转的。该列表还揭示了许多以前不知道在昼夜循环中会发生变化的基因。如THRA，这是一种甲状腺激素受体，在15种不同类型的人体组织中，于夜间达到峰值；TRIM22，会在病毒感染时表达，从而限制病毒的复制能力，并在白天达到峰值。03季节性基因表达与免疫功能有关 研究人员发现1,748个独特基因在多个组织中具有一致的季节性表达模式：春季308个，夏季361个，秋季1,072个，冬季322个。其中许多基因与免疫功能有关，它们的表达在秋季和冬季得到增强，这与病毒感染的季节性一致。一些基因还与下丘脑和垂体中激素的活性有关，如垂体激素基因在夏季达到顶峰。此外，与各种疾病相关的基因具有季节性波动，如秋季，与智力障碍有关的胶质瘤肿瘤抑制候选区域基因1（GLTSCR1）的表达在16种不同类型的组织中增加；冬季，角蛋白1（KRT1）的表达会在24种不同类型的组织中减少。小鼠中的KRT1突变与调节免疫系统异常水平蛋白质的产生以及皮肤中的异常色素沉着有关。04季节性基因表达影响中枢神经系统 季节性变化可以改变中枢神经系统内神经元和其他细胞类型的结构排列，支持神经元的星形胶质细胞的表达在秋季和冬季增加，而在夏季普遍下降。包括神经元、星形胶质细胞和少突胶质细胞在内的脑细胞的体积和相对排列在大脑的特定子区域发生了变化。05昼夜和季节性基因表达影响药效 昼夜节律影响药物效率，包括靶标和转运蛋白表达的变化。91个昼夜基因（20%）目前正被1,071种不同的药物靶向；307个季节性基因（18%）是2,632种不同药物的靶点，包括靶向16个基因的11种抗癌药物、靶向15个基因的顺铂和一种仍在临床试验阶段的抗癌药物。每种药物都可以从一天中正确的给药时间中获益。这是首个跨越多个人体组织，季节性周期，扩展了对与昼夜周期相关生理变化的转录影响理解的研究，为进一步研究人类转录组中昼夜和季节变化的影响提供了大量资源。该研究的潜在用途为靶向昼夜基因的药物给药方式可能调整为以时间依赖性剂量给药，临床试验还应考虑进行试验的昼夜和季节。该研究的共同作者Roderic Guigó博士表示：“这些发现对针对特定身体部位的特定基因给药具有重要意义。例如，在一天中的某个特定时间段，一个基因的表达量越高，阻断其作用所需的剂量就越大。给予药物的时间可以与基因表达的昼夜模式匹配。我们的发现也可能对临床试验产生影响，因为同一药物剂量的效果可能会因一年中的不同季节而改变。”责编|文竞择校对|风立宵End参考资料：[1]太阳系是扁平的？真实的太阳系模拟运动轨迹图，超出你的想象。https://www.sohu.com/a/608755018_100164427[2]Wucher V, Sodaei R, Amador R, et al. Day-night and seasonal variation of human gene expression across tissues. PLoS Biol. 2023 Feb 6;21(2):e3001986. doi: 10.1371/journal.pbio.3001986. Epub ahead of print. PMID: 36745672. 本文系生物探索原创，欢迎个人转发分享。其他任何媒体、网站如需转载，须在正文前注明来源生物探索。 往期精选 围观 ‍大龄单身的她们只想当妈妈，在“精子银行”优选未来 热文高启强同款“绝症”，超2亿人患病！Reproxalap新药申请获FDA接受，可对症治愈 热文 不沾荤腥，当心骨折！BMC：素食女性比常吃肉女性髋部骨折风险要高33%！ 热文助力生娃：生育登记取消结婚限制后，辅助生殖逐步纳入医保支付 热文 类器官发展“里程碑”！“迷你人脑”首次修复老鼠部分脑损伤 点击“阅读原文”，了解更多~

A study expands the list of known genes with circadian variation and provides the first comprehensive list of genes with seasonal variation in each tissue. Tissues in the thoracic cavity, such as the lung and heart, were most sensitive to day-night cycles, while the brain and testes were most sensitive to seasonal changes. The researchers identified 91 day-night genes and 307 seasonal genes that are known-targets for drugs, including 11 chemotherapies. The drugs could benefit from being administered in a time or season-dependent manner. The daily rotation of Earth and its yearly voyage around the Sun marks the natural rhythm of life on the planet. Human health indicators such as body temperature, blood pressure and sleep, as well as animal behaviour including foraging, moulting, mating or hibernating, is influenced by innate biological clocks that work over circadian (day-night and twenty-four hour) and/or circannual (seasons and twelve-month) cycles. A research team led by Dr. Manuel Irimia and Dr. Roderic Guigó at the Centre for Genomic Regulation (CRG) in Barcelona have published research in PLOS Biology which details how the circadian and circannual cycles influence humans at the molecular level by measuring changes to the activity of genes inside cells across different types of tissues. The researchers studied gene expression, a vital process by which the information encoded in genes is used to create useful products like proteins, which cells, tissues and organs require to stay alive and function properly. Alterations to gene expression can benefit or have adverse effects for human health, which is why researchers study which factors regulate the process to develop effective diagnostic and therapeutic strategies. The study analysed gene expression data from 46 different human tissues provided by 932 donors for the Genotype-Tissue Expression (GTEx) project, a database and tissue bank used by the scientific community to explore the effects of gene expression and variation on human health and disease. Measurements for the GTEx project are taken when a donor dies, and the authors of the study used time and season of death in the metadata of the project to assess the impact of circadian and circannual variation on gene expression across the human body. Unlike other studies that could only infer time of death, GTEx data provides the exact time -- a measurement that is important for the validity of the findings. The analysis revealed that tissues in the thoracic cavity had the largest number of day-night genes, including the lung (17.2% of all genes expressed in the tissue) and the left ventricle of the heart (19.2%), which can be explained by differences in heart rate and breathing patterns between day and night. In contrast, only 85 genes in the salivary glands showed circadian variation (0.63%), followed by 92 in the transverse colon (0.67%) and 105 in the testis (0.66%). The researchers next examined the ratio of day vs. night genes within each tissue. This revealed that the stomach has a strong diurnal preference for gene expression, whereas skin that hasn't been exposed to sun showed strongest nocturnal preferences. As expected, sun-exposed skin showed the opposite effect and had a diurnal preference, which may be because ultraviolet light alters gene expression inside cells. The authors of the study also created a list of 445 genes with a consistent day or night pattern across multiple tissues. The list includes "clock genes" already known to play an essential role in the circadian rhythm and which control when humans are awake and active.The authors found that expression variation of clock genes is also conserved in baboons and mice, although in the case of mice the clock is inverted, as expected from a nocturnal animal. The list also revealed many genes not previously known to vary during the day-night cycle. One example is THRA, a thyroid hormone receptor that was found to peak at night in 15 different types of human tissues. Another example is TRIM22, which peaks during the day and which is known to be expressed in response to viral infections, restricting their ability to replicate, for example by inhibiting the transcription of HIV-1. The effect of seasonality on gene expression revealed that twelve-month variation has a similar size of effect to 24-hour variation. The highest proportion of seasonal genes were found in the testes (25.6%) -- one of the tissues with lowest proportion of day-night genes -- followed by multiple subregions of the brain. In contrast, the left ventricle of the heart showed the lowest level of seasonality (2.8%). "We found that day-night and seasonal variation are largely uncoupled. Brain and gonadal tissues exhibited the highest seasonality, whereas those in the thoracic cavity showed stronger day-night regulation. This shows that not only genes, but also tissues, are differently affected by day-night and seasonal variation," explains ICREA Research Professor Manuel Irimia, co-author of the study and researcher at the Centre for Genomic Regulation. Most tissues did not show any bias for season-specific changes in gene expression except for the testes, which showed massive increases in gene expression during autumn and decreases in spring. The finding could reflect seasonal changes in gonadal function. The authors created a list of 1,748 unique genes with a consistent seasonal pattern across multiple tissues -- 308 in spring, 361 in summer, 1,072 in autumn and 322 in winter. Many of these genes are linked to immune function and their expression is boosted in autumn and winter, consistent with the seasonality of viral infections. Some genes were also linked to the activity of hormones in the hypothalamus and pituitary glands. For example, pituitary hormone genes peaked during the summer months. The list revealed seasonal fluctuations of genes previously linked to various disorders. For example, the expression of Glioma tumor suppressor candidate region gene 1 (GLTSCR1) increases in autumn across 16 different types of tissues, including in the brain's cerebral hemisphere. GLTSCR1 has previously been linked to intellectual disability disorders. Researchers also found that the expression of Keratin 1 (KRT1) decreases in winter across 24 different types of tissues. KRT1 mutations in mice have previously been linked to the production of abnormal levels of proteins that regulate the immune system, as well as aberrant pigmentation in skin. Previous studies have shown that seasonal changes can alter the structural arrangement of neurons and other cell types within the central nervous system. The researchers used the study to explore this at the gene expression level, and found patterns that suggest that the volume and relative arrangement of brain cells including neurons, astrocytes and oligodendrocytes change in particular subregions of the brain. For example, the expression of astrocytes, cells which support neurons, increased in autumn and winter and generally fell in summer. Further research could assess the functional impact of this finding and whether it is linked to seasonal patterns of psychiatric and brain diseases. Finally, the researchers compared their list of 445 day-night genes and the list of 1,748 seasonal genes with a database that includes known gene targets for drugs treating various types of diseases. They found that 91 day-night genes (20%) are currently being targeted by 1,071 different drugs, each of which could stand to benefit from being administered at the right time of day. They also found that 307 seasonal genes (18%) are targeted by 2,632 different drugs, each of which could stand to benefit from being administered at the right season -- summer, autumn, winter or spring. This included 11 anticancer drugs including bortezomib, which targets 16 genes and cisplatin, which targets 15. It also included an anticancer drug still in clinical trial phase. "These findings have implications for administering drugs that target specific genes in specific body parts. For example, the higher the expression of a gene during a particular time of day, the larger dose is required to block their action. Administering a drug could be timed to best match the circadian pattern of gene expression. Our findings could also have an impact on clinical trials, as the effect of the same drug dose may change depending on the season of the year," says Dr. Roderic Guigó, co-author of the study and researcher at the Centre for Genomic Regulation.