Chromatin connects metabolism to circadian gene regulation in the aging eye

染色质将新陈代谢与衰老眼睛的昼夜节律基因调控联系起来

• 批准号: 10585177
• 负责人: Vikki Marie Weake
• 金额: $ 37.38万
• 依托单位: PURDUE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-01 至 2026-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10585177
• 关键词: ARNTL gene; Adenosylhomocysteinase; Affect; Age; Age of Onset; Aging; Alternative Splicing; Amino Acids; Binding; Biological Models; Biological Rhythm; Caloric Restriction; Carbon; Cell Survival; Cells; Chromatin; Circadian Dysregulation; Circadian Rhythms; Cysteine; DNA Methylation; Data; Deposition; Development; Diabetic Retinopathy; Drosophila eye; Drosophila genus; Elderly; Embryo; Enzymes; Epigenetic Process; Event; Exposure to; Eye; Eye diseases; Feedback; Fibroblasts; Folic Acid; Gene Expression; Gene Expression Profile; Gene Expression Regulation; Genes; Genetic Transcription; Glaucoma; Global Change; Health; Hepatocyte; Histones; Human; Intake; Light; Link; Longevity; Messenger RNA; Metabolic; Metabolic Pathway; Metabolism; Methionine; Methionine Metabolism Pathway; Methylation; Methyltransferase; Modeling; Mus; Myopia; Orthologous Gene; Output; Oxidative Stress; Pathway interactions; Periodicity; Phase; Photoreceptors; Phototransduction; Play; Publishing; RNA Splicing; Reactive Oxygen Species; Retinal Cone; Retinal Degeneration; Risk; Role; S-Adenosylhomocysteine; S-Adenosylmethionine; Series; Structure; Study models; Testing; Time; Translations; Vertebrates; Visual; age related; cell type; circadian; circadian pacemaker; circadian regulation; epigenome; fly; gene regulatory network; genetic manipulation; genome-wide; histone methylation; histone methyltransferase; in vitro activity; knock-down; metabolic abnormality assessment; neuroprotection; normal aging; premature; prevent; programs; protein expression; transcription factor; transcriptome; transcriptome sequencing; whole genome

Changes in metabolism in the aging eye can affect its epigenome because several metabolic intermediates also act as donor molecules for deposition of epigenetic marks such as histone and DNA methylation. During aging, there are changes in the metabolic pathways that produce the donor molecule required for histone and DNA methylation, S-adenosylmethionine (SAM), from the amino acid methionine. Methionine metabolism is strongly linked to aging across multiple species because restricting methionine intake extends lifespan, and is thought to be responsible for the lifespan extension caused by caloric restriction. In the aging Drosophila eye, we observe changes in methionine metabolism including an increase in levels of S-adenosylhomocysteine (SAH), which inhibits the activity of methyltransferases. This age-associated increase in SAH correlates with decreased levels of histone methylation marks across the entire genome in photoreceptors. Moreover, we show that loss of the methyltransferases that deposit one of these marks in photoreceptors leads to premature retinal degeneration. We propose that the decreased histone methylation in aging photoreceptors contributes to the age-related changes that we observe in gene expression. Specifically, we have identified changes in rhythmic expression of more than a third of active genes in aging photoreceptors together with altered transcription factor binding activity of the circadian master regulators Clock and Cycle. The circadian clock is highly conserved from flies to humans, and maintains biological rhythms by controlling gene expression programs through a series of transcription- translation feedback loops. When we disrupt the circadian clock in photoreceptors, we observe substantial retinal degeneration accompanied by global changes in chromatin accessibility and misregulation of more than a quarter of active genes. Loss of circadian regulators in the mouse eye causes age-dependent retinal degeneration, suggesting that the circadian clock has a conserved role in protecting the aging eye. Based on our preliminary data, we hypothesize that increasing oxidative stress in the aging eye inhibits activity of the sole enzyme that breaks down SAH on chromatin at actively expressed genes. We further propose that the local increases in SAH levels at expressed genes inhibit the activity of histone methyltransferases, leading to changes in the rhythmic expression of genes in the aging eye. Together, these studies provide a framework in which to understand how the normal changes that occur in the aging eye can disrupt its metabolism, leading to changes in the epigenome that disrupt normal patterns of gene expression and increase the risk of ocular disease. Drosophila provides an ideal model for these studies because it shares a similar circadian clock and epigenetic mechanisms with humans, but ages much more rapidly allowing us to examine mechanisms in the context of normal aging in specific cell types in the eye.

衰老眼睛中代谢的变化可以影响其表观基因组，因为几种代谢中间体也 作为供体分子沉积表观遗传标记，如组蛋白和DNA甲基化。在老化过程中， 产生组蛋白和DNA所需供体分子的代谢途径发生了变化 甲基化，S-腺苷甲硫氨酸（SAM），来自氨基酸甲硫氨酸。甲硫氨酸代谢强烈 与多个物种的衰老有关，因为限制蛋氨酸的摄入可以延长寿命， 负责热量限制导致的寿命延长。在衰老的果蝇眼睛中，我们观察到 甲硫氨酸代谢的变化，包括S-腺苷高半胱氨酸（SAH）水平的增加， 抑制甲基转移酶的活性。这种与年龄相关的SAH增加与降低的水平相关， 组蛋白甲基化标记在光感受器的整个基因组中。此外，我们表明，损失的 在光感受器中存款这些标记之一的甲基转移酶导致过早的视网膜变性。 我们认为衰老光感受器中组蛋白甲基化的降低有助于与年龄相关的 我们在基因表达中观察到的变化。具体来说，我们已经确定了节奏表达的变化， 在老化的光感受器中，超过三分之一的活性基因连同改变的转录因子结合活性 昼夜节律主调节器时钟和周期。从苍蝇到人类，生物钟都是高度保守的， 并通过一系列转录控制基因表达程序来维持生物节律， 翻译反馈回路当我们破坏光感受器的生物钟时，我们观察到大量的视网膜 变性伴随着染色质可及性的全面变化和超过一个 四分之一的活跃基因小鼠眼内昼夜节律调节器的缺失导致年龄依赖性视网膜病变 这表明生物钟在保护衰老的眼睛方面具有保守的作用。基于 根据我们的初步数据，我们假设衰老眼睛中氧化应激的增加抑制了鞋底的活性。 在活跃表达基因的染色质上分解SAH的酶。我们进一步建议， 在表达基因中SAH水平的增加抑制了组蛋白甲基转移酶的活性， 基因的节律性表达。总之，这些研究提供了一个框架， 了解衰老眼睛中发生的正常变化如何破坏其新陈代谢，导致变化 在表观基因组中，破坏了基因表达的正常模式，增加了眼部疾病的风险。 果蝇为这些研究提供了一个理想的模型，因为它具有相似的昼夜节律钟和表观遗传学特征。 机制与人类，但年龄更快，使我们能够检查机制的背景下， 眼睛中特定细胞类型的正常老化。