Chromatin connects metabolism to circadian gene regulation in the aging eye

老化眼睛的新陈代谢变化会影响其表观基因组，因为几种代谢中间产物也 作为表观遗传标记沉积的供体分子，如组蛋白和DNA甲基化。在衰老过程中， 产生组蛋白和dna所需的供体分子的代谢途径发生了变化。 甲基化，S-腺苷蛋氨酸(SAM)，由蛋氨酸的氨基酸组成。蛋氨酸代谢很强 与多种物种的衰老有关，因为限制蛋氨酸摄入量延长了寿命，并被认为 对卡路里限制导致的寿命延长负责。在果蝇老化的眼睛里，我们观察到 蛋氨酸代谢的变化，包括S同型半胱氨酸水平升高， 抑制甲基转移酶的活性。这种与年龄相关的SAH增加与水平的下降相关 光感受器中整个基因组的组蛋白甲基化标记。此外，我们还表明， 在光感受器中沉积这些标记之一的甲基转移酶会导致视网膜过早退化。 我们认为，衰老光感受器中组蛋白甲基化水平的降低与年龄相关 我们在基因表达上观察到的变化。具体地说，我们已经确定了节律性表达的变化 衰老光感受器中超过三分之一的活性基因与转录因子结合活性改变 昼夜节律的主要调节器的时钟和周期。从苍蝇到人类，生物钟都高度保守， 并通过一系列转录控制基因表达程序来维持生物节律- 翻译反馈循环。当我们打乱光感受器的生物钟时，我们观察到大量的视网膜 伴随着染色质可及性的全球变化和超过一年的失调 四分之一的活跃基因。小鼠眼球昼夜节律的丧失导致年龄相关性视网膜 退化，这表明生物钟在保护老化的眼睛方面具有保守的作用。基于 我们的初步数据假设，老化的眼睛中不断增加的氧化应激会抑制脚底的活动 在活跃表达的基因上分解染色质上的SAH的酶。我们进一步建议，当地的 表达基因上SAH水平的增加抑制了组蛋白甲基转移酶的活性，导致了变化 在老化的眼睛中基因的有节奏的表达。总而言之，这些研究提供了一个框架，在其中 了解老化眼睛中发生的正常变化如何扰乱其新陈代谢，从而导致变化 在表观基因组中，这会扰乱正常的基因表达模式，增加患眼病的风险。 果蝇为这些研究提供了一个理想的模型，因为它共享相似的生物钟和表观遗传学 与人类有关的机制，但衰老速度更快，使我们能够在 眼睛中特定细胞类型的正常衰老。

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.