Epigenetic control of seasonal timing

季节时间的表观遗传控制

• 批准号: BB/K003119/1
• 负责人: Andrew Loudon
• 金额: $ 56.02万
• 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: 2013
• 资助国家: 英国
• 起止时间: 2013 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FK003119%2F1
• 关键词: Epigenetic; control; seasonal; timing

Animals inhabiting seasonal environments need to adapt their physiology to survive to anticipate environmental change. To achieve this, sophisticated internal clockworks have evolved which drives annual cycles of behaviour and physiology. These can free-run in constant conditions ("circannual" rhythms) and are synchronised to the environment by a brain hormone Melatonin (MEL), produced at night from the pineal gland, the activity of which is regulated by the light-dark cycle. Accordingly, MEL targets are exposed to seasonal changes in duration of the MEL signal - long in winter and short in summer. The MEL signal acts on hormone secreting circuits (neuroendocrine), which in turn drive annual reproductive and metabolic cycles. MEL acts on targets sites in a specific region at the base of the brain in the pituitary gland called the pars tuberalis (PT), which acts as a seasonal conductor - controlling hormone secretion such as prolactin (a hair growth regulator) in the main pituitary gland, and also within another immediately adjacent brain structure in the hypothalamus, where it regulates the thyroid hormone levels, controlling seasonal reproduction and metabolic cycles. We discovered a key gene regulating long-photoperiod (LP) responses in the PT called EYA3 which is rapidly activated by LP's and acts as a switch mechanism driving hypothalamic thyroid hormone changes. We have also discovered many genes in the PT are regulated by a process called DNA methylation. Methylation suppresses activity of genes and is essential to the function of normal cells. Our studies show that both de-methylation - removal of the suppressive imprint - and methylation - imposition of the imprint - are remarkably dynamic. So much so, that each night MEL induces changes affecting the methylated state of over 1000 genes. Such DNA modifications are termed epigenetic - heritable changes caused by mechanisms other than changes in the underlying DNA sequence, and are crucial in many diseases, but also underpins normal physiology including ageing and differentiation of stem cells. We aim to map all methylated sites in the sheep genome (the "methylome") in response to seasonal signals (the "seasonal-methylome"), simulated by changes in photoperiod using high-resolution bisulphite sequencing. This is important, as our current methylation screen was based on a low-resolution and less sensitive method that cannot identify specific methylated DNA nucleotides. We will now be able to define methylation changes that affect the function of specific DNA signals, such as binding sites for specific transcriptional regulators. We will compare material collected from animals maintained on short or long photoperiods, using tissue from the PT and also the ventral hypothalamus (where thyroid hormone metabolism is controlled), and examine how the methylome changes in different photoperiods. The pattern of methylation under different photoperiods will also be correlated with changes in the expression of genes, determined by whole genome RNA Sequencing (the "seasonal-transcriptome"). We will test the hypothesis that pre-exposure to specific photoperiods can affect an animal's response to changes in photoperiod, and how the "methylome" drives long-term seasonal rhythms. These studies will provide the first insight into epigenetic control of genes in brain structures that control seasonal reproduction and growth in a mammal. Our studies may also reveal general features of the biology of livestock domestication, since components of the PT circuit (TSH-R) have been identified as being under strong selection in comparative studies of chickens. This may lead to new understanding of mechanisms controlling reproduction and growth, of commercial significance to the livestock industry in the UK, and reveal how animals could adapt to climate change through interaction of external signals in the environment, and DNA modifications.

生活在季节性环境中的动物需要调整自己的生理机能以适应环境的变化。为了实现这一目标，复杂的内部时钟系统已经进化出来，它驱动着行为和生理的年度周期。它们可以在固定的条件下自由运行（“年周期”节律），并通过夜间由松果体产生的脑褪黑激素（MEL）与环境同步，松果体的活动受昼夜循环的调节。因此，MEL目标暴露于MEL信号持续时间的季节性变化-冬季长，夏季短。MEL信号作用于激素分泌回路（神经内分泌），进而驱动每年的生殖和代谢周期。MEL作用于脑垂体底部一个叫做结节部（PT）的特定区域的目标部位，它作为一个季节性的导体——控制激素的分泌，如垂体主腺中的催乳素（一种毛发生长调节剂），以及下丘脑中另一个紧邻的大脑结构，在那里它调节甲状腺激素水平，控制季节性的繁殖和代谢周期。我们在PT中发现了一个调节长光周期（LP）反应的关键基因EYA3，该基因被LP快速激活，并作为驱动下丘脑甲状腺激素变化的开关机制。我们还发现，PT中的许多基因受到DNA甲基化过程的调节。甲基化抑制基因的活性，对正常细胞的功能至关重要。我们的研究表明，去甲基化（去除抑制印记）和甲基化（施加印记）都是非常动态的。如此之多，以至于每晚MEL都会引起影响1000多个基因甲基化状态的变化。这种DNA修饰被称为表观遗传-由潜在DNA序列变化以外的机制引起的可遗传变化，在许多疾病中至关重要，但也是包括衰老和干细胞分化在内的正常生理的基础。我们的目标是绘制绵羊基因组中所有甲基化位点（“甲基组”），以响应季节信号（“季节性甲基组”），通过使用高分辨率亚硫酸盐测序模拟光周期的变化。这很重要，因为我们目前的甲基化筛选是基于一种低分辨率和不太敏感的方法，不能识别特定的甲基化DNA核苷酸。我们现在将能够定义影响特定DNA信号功能的甲基化变化，例如特定转录调节因子的结合位点。我们将比较从维持在短光周期和长光周期的动物身上收集的材料，使用来自PT和下丘脑腹侧（甲状腺激素代谢控制的地方）的组织，并研究甲基组在不同光周期下的变化。不同光周期下的甲基化模式也将与基因表达的变化相关，由全基因组RNA测序（“季节性转录组”）确定。我们将测试预先暴露于特定光周期可以影响动物对光周期变化的反应的假设，以及“甲基组”如何驱动长期的季节性节律。这些研究将首次深入了解控制哺乳动物季节性繁殖和生长的大脑结构中基因的表观遗传控制。我们的研究还揭示了家畜驯化生物学的一般特征，因为在鸡的比较研究中已经确定了PT回路（TSH-R）的组成部分受到强烈的选择。这可能会导致对控制繁殖和生长机制的新理解，对英国畜牧业具有商业意义，并揭示动物如何通过环境中外部信号的相互作用和DNA修饰来适应气候变化。

项目成果

Effects of Spring Warming on Seasonal Neuroendocrinology and Activation of the Reproductive Axis in Hibernating Arctic Ground Squirrels.

春季变暖对冬眠北极地松鼠季节性神经内分泌和生殖轴激活的影响。

• DOI: 10.1093/icb/icac112
• 发表时间: 2022
• 期刊: Integrative and comparative biology
• 影响因子: 2.6
• 作者: Chmura HE

Looking inside the seasonal clock.

观察季节性时钟的内部。

• DOI: 10.1111/jne.12238
• 发表时间: 2015
• 期刊: Journal of neuroendocrinology
• 影响因子: 3.2
• 作者: Lincoln G

Npas4 is activated by melatonin, and drives the clock gene Cry1 in the ovine pars tuberalis.

NPAS4被褪黑激素激活，并驱动卵形pars tuberalis中的时钟基因Cry1。

• DOI: 10.1210/me.2012-1366
• 发表时间: 2013-06
• 期刊: Molecular endocrinology (Baltimore, Md.)
• 作者: West A;Dupré SM;Yu L;Paton IR;Miedzinska K;McNeilly AS;Davis JR;Burt DW;Loudon AS
• 通讯作者: Loudon AS

An epithelial circadian clock controls pulmonary inflammation and glucocorticoid action.

• DOI: 10.1038/nm.3599
• 发表时间: 2014-08
• 期刊: Nature medicine
• 影响因子: 82.9

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