Unravelling the networks that regulate seasonal rhythmicity in the epigenome

揭示表观基因组中调节季节节律的网络

• 批准号: BB/N015584/1
• 负责人: Andrew Loudon
• 金额: $ 60.48万
• 依托单位: University of Manchester
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2016
• 资助国家: 英国
• 起止时间: 2016 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FN015584%2F1
• 关键词: Unravelling; networks; regulate; seasonal; rhythmicity

Two interacting rhythmical processes dominate the biology of most organisms on earth. The best studied is the circadian clock, which this has evolved to match the 24h rotation of earth. The second is the circannual clock driving ca 1-year rhythms, which has evolved in many life-forms to meet the profound environmental challenges of a seasonal planet. Although the two clock-work systems are interlocked, the precise mechanisms by which the circadian clock contributes to a seasonal response are yet to be established in any animal species, nor do we know how long-term circannual rhythm generation occurs.The seasonal and circannual timing mechanisms have been studied in sheep. Our work and others has defined how the nocturnal hormone melatonin is used by the neuroendocrine system to provide an internal representation of external photoperiod, driving seasonal reproductive and metabolic responses. A key site of action is the pituitary gland, called pars tuberalis (PT), in a region immediately adjacent to the hypothalamus, where a local circadian clock-gene rhythm is entrained each night by the daily melatonin hormone signal in specialized thyroid-stimulating hormone (TSH) expressing cells. These PT thyrotrophs have been termed "calendar cells". Here, a key transcriptional co-activator (EYA3) is rhythmically regulated, and on long summer photoperiods (LP) is strongly augmented, leading to expression of PT TSH, which activates TSH-receptors and thyroid hormone (TH) metabolism in the adjacent hypothalamus. The TH-dependency for the seasonal response is a conserved feature of the biology of vertebrate species. We have now shown that hormone packaging protein (CHGA) is induced on short winter photoperiods (SP) and that specialised cells within the PT flip from a CHGA to an EYA3 state (binary switching) over the circannual cycle.Our goal is to discover whether an "epigenetic" process underpins this binary switch and whether this switch drives long-term rhythm generation. Epigenetics is defined as the structural adaptation of chromosomal regions so as to register, signal or perpetuate altered activity states without changes to DNA sequence. It involves modification of histone proteins around which DNA is wrapped, and also the chemical nature (methylation) of one of the DNA nucleotides (cytosine). Our work builds in part on recently tested theoretical models developed by plant scientists studying vernalisation, which has revealed a critical role for histone-modifying enzyme complex (polycomb repressor-2, PRC2) in providing a memory of winter cold-exposure. PRC2 represses gene expression by acting on histone-3 proteins. A key element of the PRC2 complex (EZH2) is activated on LP, and we will test whether this is involved in a global suppression of SP-expressed genes, including CHGA. We now have exciting new evidence that EZH2 also activates EYA3 on LP, via the circadian clock. This leads us to the hypothesis that chromatin modifying enzymes act as binary switches, activating LP-genes, and suppressing SP-genes. This could be the long-predicted biochemical switch mechanism driving circannual cycles in vertebrates. We investigate this switch mechanism in cell models, and also using cells and tissues from sheep over the circannual cycle. This will include studies of how protein modifications and partners of EZH2 are involved. This will allow us to test this hypothesis that changes in histone-3 protein methylation (driven by EZH2) drives the circannual cycle by mapping these to underlying changes the PT. Finally, we will combine our findings with existing genomic data sets for domesticated and wild sheep breeds, and establish whether genetic circuits driving timing have been selected in course of domestication. Thus, we aim to unravel the central pathways driving the seasonal rhythm of life on our planet.

两个相互作用的有节奏的过程支配着地球上大多数生物的生物学。研究得最好的是生物钟，它已经进化到与地球自转24小时相匹配。第二个是驱动1年周期的年轮，它在许多生命形式中进化，以应对季节性星球带来的深刻环境挑战。尽管这两种生物钟系统是相互关联的，但在任何动物物种中，生物钟对季节性反应的精确机制尚未建立，我们也不知道长期的周期节律是如何产生的。研究了羊的季节和年际节律机制。我们和其他人的工作已经定义了夜间激素褪黑素是如何被神经内分泌系统用来提供外部光周期的内部表征，驱动季节性生殖和代谢反应的。一个关键的作用部位是垂体，被称为结节部（PT），它位于紧邻下丘脑的区域，在那里，一个局部的生物钟基因节律每天晚上被专门的促甲状腺激素（TSH）表达细胞中的每日褪黑激素信号所引导。这些促甲状腺细胞被称为“日历细胞”。在这里，一个关键的转录共激活因子（EYA3）被有节奏地调节，并且在长夏季光周期（LP）上被强烈增强，导致PT TSH的表达，从而激活邻近下丘脑的TSH受体和甲状腺激素（TH）代谢。对季节反应的th依赖性是脊椎动物物种生物学的一个保守特征。我们现在已经证明，激素包装蛋白（CHGA）在短冬季光周期（SP）下被诱导，并且PT内的特化细胞在一个周期内从CHGA状态翻转到EYA3状态（二进制开关）。我们的目标是发现“表观遗传”过程是否支持这种二进制开关，以及这种开关是否驱动长期节律的产生。表观遗传学被定义为染色体区域的结构适应性，以便在不改变DNA序列的情况下记录，发出信号或使改变的活性状态永久存在。它涉及到包裹DNA的组蛋白的修饰，以及DNA核苷酸之一（胞嘧啶）的化学性质（甲基化）。我们的工作部分建立在最近由研究春化的植物科学家开发的经过测试的理论模型上，该模型揭示了组蛋白修饰酶复合物（polycomb repressor-2, PRC2）在提供冬季寒冷暴露记忆方面的关键作用。PRC2通过作用于组蛋白3抑制基因表达。PRC2复合体（EZH2）的一个关键元件在LP上被激活，我们将测试这是否参与sp表达基因的全局抑制，包括CHGA。我们现在有令人兴奋的新证据表明EZH2也通过生物钟激活LP上的EYA3。这导致我们假设染色质修饰酶作为二进制开关，激活lp基因，抑制sp基因。这可能是长期预测的生物化学开关机制，驱动脊椎动物的年循环。我们在细胞模型中研究了这种开关机制，并使用了绵羊的细胞和组织进行循环。这将包括研究EZH2的蛋白质修饰和伴侣是如何参与的。这将使我们能够通过将组蛋白-3蛋白甲基化的变化（由EZH2驱动）映射到PT的潜在变化来验证这一假设，即组蛋白-3蛋白甲基化的变化驱动了年循环。最后，我们将把我们的发现与驯化和野生绵羊品种的现有基因组数据集结合起来，并确定遗传回路驱动时间是否在驯化过程中被选择。因此，我们的目标是解开驱动地球上生命季节性节奏的主要途径。

项目成果

Gerald Lincoln: A man for all seasons.

杰拉德·林肯：四季皆宜的男人。

• DOI: 10.1111/jne.12968
• 发表时间: 2021
• 期刊: Journal of neuroendocrinology
• 影响因子: 3.2
• 作者: Ebling FJP

Circadian clock mechanism driving mammalian photoperiodism

驱动哺乳动物光周期的昼夜节律时钟机制

• DOI: 10.1038/s41467-020-18061-z
• 发表时间: 2020
• 期刊: Nature Communications
• 影响因子: 16.6
• 作者: Wood S

Reproducibility of CRISPR-Cas9 methods for generation of conditional mouse alleles: a multi-center evaluation

• DOI: 10.1186/s13059-019-1776-2
• 发表时间: 2019-08-26
• 期刊: GENOME BIOLOGY
• 影响因子: 12.3
• 作者: Gurumurthy, Channabasavaiah B.;O'Brien, Aidan R.;Burgio, Gaetan
• 通讯作者: Burgio, Gaetan

Immunity around the clock.

全天候免疫。

• DOI: 10.1126/science.aah4966
• 发表时间: 2016-11-25
• 期刊: Science (New York, N.Y.)
• 作者: Man K;Loudon A;Chawla A
• 通讯作者: Chawla A

Hypothalamic remodeling of thyroid hormone signaling during hibernation in the arctic ground squirrel.

• DOI: 10.1038/s42003-022-03431-8
• 发表时间: 2022-05-23
• 期刊: Communications biology
• 影响因子: 5.9