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.

衰老眼的新陈代谢的变化可能会影响其表观基因组，因为几个代谢中间体也会影响 充当表观遗传标记（例如组蛋白和DNA甲基化）沉积的供体分子。在衰老期间， 产生组蛋白和DNA所需的供体分子的代谢途径发生了变化 来自氨基酸蛋氨酸的甲基化，S-腺苷甲硫代（SAM）。蛋氨酸代谢强烈 与多种物种的衰老有关，因为限制蛋氨酸的摄入延长了寿命，被认为是 负责热量限制引起的寿命延长。在老化的果蝇眼中，我们观察到 蛋氨酸代谢的变化，包括s-腺苷甲基瘤半胱氨酸（SAH）的水平增加，这 抑制甲基转移酶的活性。这种与年龄相关的SAH的增加与水平降低相关 光感受器中整个基因组中的组蛋白甲基化标记。此外，我们表明了损失 将这些标记之一沉积在感光器中的甲基转移酶会导致过早的视网膜变性。 我们提出，衰老感光体中的组蛋白甲基化降低有助于年龄相关 我们在基因表达中观察到的变化。具体而言，我们已经确定了节奏表达的变化 超过三分之一的活性基因与转录因子结合活性改变 昼夜节律监管机的时钟和周期。昼夜节律从苍蝇到人类高度保守， 并通过通过一系列转录来控制基因表达程序来维持生物节律 - 翻译反馈循环。当我们在感光器中破坏昼夜节律时钟时，我们会观察到大量的视网膜 堕落伴随着染色质可及性的全球变化，而不仅仅 活性基因的四分之一。小鼠眼中昼夜节律调节剂的损失会导致年龄依赖性视网膜 退化，表明昼夜节律在保护衰老眼中具有保守的作用。基于 我们的初步数据，我们假设在衰老眼中增加氧化应激会抑制唯一的活性 在积极表达的基因上分解在染色质上的SAH的酶。我们进一步建议当地 在表达基因处的SAH水平升高抑制组蛋白甲基转移酶的活性，导致变化 在衰老眼中基因的节奏表达中。这些研究共同提供了一个框架 了解衰老眼中发生的正常变化如何破坏其新陈代谢，导致变化 在破坏基因表达正常模式并增加眼部疾病风险的表观基因组中。 果蝇为这些研究提供了理想的模型，因为它具有类似的昼夜节律和表观遗传学 具有人类的机制，但更快地使我们能够在 眼睛中特定细胞类型的正常衰老。