Precision pharmacological reversal of strain-specific diet-induced metabolic syndrome in mice informed by epigenetic and transcriptional regulation.
Precision pharmacological reversal of strain-specific diet-induced metabolic syndrome in mice informed by epigenetic and transcriptional regulation.
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菌株特异性饮食诱导的代谢综合征的精确药理逆转，这些小鼠的表观遗传学和转录调节导致。
DOI：
10.1371/journal.pgen.1010997
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发表时间：
2023-10
期刊：
影响因子：
4.5
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中科院分区：
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在美国，与饮食有关的代谢综合征是危害健康的最大因素。然而，基因-环境相互作用及其表观基因组和转录组整合的研究由于缺乏在小鼠模型中可能的人类环境和遗传控制而变得复杂。本研究将C57BL/6J （BL6）、A/J和NOD/ShiLtJ （NOD）三种小鼠品系暴露于高脂肪、高碳水化合物饮食中，导致不同程度的代谢综合征。然后，我们对每个菌株进行转录组学和全基因组DNA甲基化分析，发现在不一致代谢表型的上游，基因表达和甲基化发生了重叠但也高度不同的变化。对饮食影响的菌株特异性途径分析显示，所有三种菌株都存在胆固醇生物合成失调，但驱动这种失调的调节网络不同。这提示了一种菌株特异性靶向药物干预策略，这些上游调节因子由表观遗传和转录调节通知。作为一项试点研究，我们给药GW4064靶向其中一个基因型依赖网络，即farnesoid X受体途径，并发现GW4064对BL6的饮食影响具有菌株特异性保护，正如我们的转录组学分析所预测的那样。此外，GW4064治疗诱导NOD炎症相关基因表达变化，表明其相关毒性和治疗效果具有菌株特异性作用。这项初步研究证明了精确治疗方法在基因型知情饮食代谢干预中的潜在功效，并为指导这种方法提供了一个小鼠平台。代谢综合征是世界范围内发病率和死亡率的主要原因。这种疾病受到遗传和环境暴露的影响，尤其是饮食。这种效应被称为“基因-饮食”的相互作用，表明治疗代谢综合征的最佳饮食建议和治疗干预可能在遗传亚群之间存在显著差异。在这里，我们分析了基因上不同的小鼠品系，它们对高脂肪、高碳水化合物的美国饮食表现出不同程度的代谢综合征。虽然在所有三种菌株中，相似的生物过程都受到饮食变化的影响，但我们观察到菌株特有的某些分子途径的表观遗传和转录调节的破坏，从而允许菌株特异性治疗平台旨在重建这些被破坏的分子途径之一的正常功能。事实上，所选药物的应用显著降低了美国饮食在预测菌株中的代谢效应，而其他测试菌株显示出炎症反应基因的活性增加，证明了该药物的功效及其相关毒性的菌株特异性。这项初步研究强调了精确治疗在代谢综合征治疗中的价值，并强调了在临床前药物试验中使用多种遗传不同的小鼠品系的优势，以帮助确定疗效和毒性的遗传依赖性。
Diet-related metabolic syndrome is the largest contributor to adverse health in the United States. However, the study of gene-environment interactions and their epigenomic and transcriptomic integration is complicated by the lack of environmental and genetic control in humans that is possible in mouse models. Here we exposed three mouse strains, C57BL/6J (BL6), A/J, and NOD/ShiLtJ (NOD), to a high-fat, high-carbohydrate diet, leading to varying degrees of metabolic syndrome. We then performed transcriptomic and genome-wide DNA methylation analyses for each strain and found overlapping but also highly divergent changes in gene expression and methylation upstream of the discordant metabolic phenotypes. Strain-specific pathway analysis of dietary effects revealed a dysregulation of cholesterol biosynthesis common to all three strains but distinct regulatory networks driving this dysregulation. This suggests a strategy for strain-specific targeted pharmacologic intervention of these upstream regulators informed by epigenetic and transcriptional regulation. As a pilot study, we administered the drug GW4064 to target one of these genotype-dependent networks, the farnesoid X receptor pathway, and found that GW4064 exerts strain-specific protection against dietary effects in BL6, as predicted by our transcriptomic analysis. Furthermore, GW4064 treatment induced inflammatory-related gene expression changes in NOD, indicating a strain-specific effect in its associated toxicities as well as its therapeutic efficacy. This pilot study demonstrates the potential efficacy of precision therapeutics for genotype-informed dietary metabolic intervention and a mouse platform for guiding this approach. Metabolic syndrome is a major contributor to worldwide morbidity and mortality. This disorder is influenced by both genetics and environmental exposures, particularly diet. Such an effect, known as a “gene-by-diet” interaction, suggests that optimal dietary recommendations and therapeutic interventions for treating metabolic syndrome may differ dramatically between genetic sub-populations. Here, we have analyzed genetically distinct mouse strains which exhibit varying degrees of metabolic syndrome in response to a high-fat, high-carbohydrate American diet. While similar biological processes were affected by the change in diet in all three strains, we observed a strain-unique disruption of epigenetic and transcriptional regulation of certain molecular pathways, allowing for a strain-specific therapeutic platform aimed to re-establish normal functionality of one of these disrupted molecular pathways. Indeed, application of the chosen drug significantly decreased the observed metabolic effects of the American diet in only the predicted strain while the other tested strain exhibited increased activity of inflammatory response genes, demonstrating the strain-specificity of this drug’s efficacy as well as its associated toxicities. This pilot study highlights the value of precision therapeutics in the treatment of metabolic syndrome and underscores the advantage of using multiple genetically distinct strains of mice in preclinical drug trials to help identify genetic dependencies in efficacy and toxicity.