Link between epigenetic modifiers and fat metabolism for healthy aging

表观遗传修饰剂与健康老龄化脂肪代谢之间的联系

基本信息

批准号：
9923525
负责人：
ANNE BRUNET
金额：
$ 41.45万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-01 至 2022-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9923525
关键词：
Acids Age Atherosclerosis Binding Proteins Buffers Caenorhabditis elegans Cells Chromatin Remodeling Factor Communication Complex Coupled Critical Pathways Data Defect Diabetes Mellitus Diet Dietary Fatty Acid Dietary Supplementation Disease Enzymes Epigenetic Process Evolution Exhibits FRAP1 gene Fatty Acid Desaturases Fatty Acids Fatty acid glycerol esters Foundations Gas Chromatography Generations Genes Genetic Genetic Transcription Gonadal structure HMGB1 Protein Health Health Promotion Histone H3 Homeostasis Human Individual Inherited Intestines Lead Link Longevity Lysine Mass Spectrum Analysis Membrane Metabolic Methyltransferase Modeling Molecular Monounsaturated Fatty Acids Nutrient Oleic Acids Organism Outcome Output PPAR alpha Parents Pathway interactions Physiological Publishing Reactive Oxygen Species Regulation Role Signal Transduction Signaling Molecule Steroids Stimulus Testing Tissues Transcend Unsaturated Fatty Acids Work base chromatin remodeling desaturase environmental change experimental study fatty acid metabolism fatty acid supplementation healthspan healthy aging insight lipid metabolism mTOR Signaling Pathway monounsaturated fat neuronal cell body next generation novel palmitoleic acid response transcription factor transgenerational epigenetic inheritance

项目摘要

PROJECT SUMMARY Chromatin modifiers integrate environmental stimuli to physiological outputs via epigenetic changes, which can be long lasting and even transcend generations. Chromatin remodeling has been found to extend lifespan in several organisms, but how chromatin modifiers promote longevity is unknown. We have made the tantalizing observation that deficiency in the COMPASS methyltransferase complex, which trimethylates histone H3 at lysine 4 (H3K4me3), leads to lifespan extension in C. elegans that is causally coupled to changes in fat metabolism. Intriguingly, H3K4me3 modifiers act in the germline of C. elegans to trigger fat metabolism changes in somatic tissues, suggesting a non-cell autonomous signaling between germline and soma for fat metabolism. Using high throughput mass spectrometry, we find H3K4me3-methyltransferase deficient worms are enriched for several specific mono-unsaturated fatty acids (MUFAs): oleic acid, palmitoleic acid, and cis- vaccenic acid. This fat metabolic switch to MUFAs requires a conserved network involving the transcription factors SPB-1/SREBP1, NHR-49/PPARα, and delta-9 fatty acid desaturases, and remarkably endogenous MUFA accumulation is necessary for lifespan extension. Interestingly, dietary supplementation of individual MUFAs is sufficient to extend lifespan in worms. Excessive fat storage has been associated with diseases such as atherosclerosis and diabetes, but our data suggest fat composition is critical, and that epigenetic remodeling can result in specific fatty acids that increase longevity. Because the genes that generate unsaturated fatty acids are highly conserved throughout evolution, endogenous or dietary MUFAs could promote longevity in humans. Exciting new questions raised by these observations are: how is MUFA metabolism influenced by epigenetic changes and environmental stimuli? How is the communication between germline and somatic tissues orchestrated to influence fat composition? Are the changes in fat composition inherited in the progeny in a transgenerational manner? And how do MUFAs act to extend lifespan? C. elegans is an excellent model for fat metabolism because of its genetic power and because the machinery for conversion of saturated to unsaturated fatty acids is entirely conserved. This proposal will test the hypothesis that epigenetic changes in H3K4me3 in the germline initiates a signal that induces a switch to MUFA accumulation in specific somatic tissues, resulting in lifespan extension. Three specific aims will be developed to test this new idea: 1. To determine how germline H3K4me3 modifiers lead to change in somatic fat composition in parents and progeny. 2. To identify the molecular mechanisms that induce a switch to mono-unsaturated fatty acids and longevity in response to altered germline H3K4me3 and environmental stimuli. 3. To characterize the regulation and mode of action of specific fatty acids that promote longevity. These studies will give mechanistic insights into specific fat metabolism regulation in the germline and potentially discover new signaling molecules that inform the soma of the metabolic status of the germline. Furthermore, the proposed experiments will identify the critical pathways linking epigenetic changes to fat metabolism across generations. Finally, this work in C. elegans will determine how fat metabolism can have benefits on healthspan and lifespan, and provide the foundation to test the conserved role of MUFA metabolism in other species.

项目摘要染色质修饰符通过表观遗传变化将环境刺激整合到物理输出中，这可以持久甚至超越世代。已经发现染色质重塑可以延长寿命几种生物，但是染色质修饰剂如何促进寿命是未知的。我们使诱人观察到指南赖氨酸4（H3K4ME3），导致秀丽隐杆线虫的寿命延伸，有时与脂肪的变化耦合代谢。有趣的是，H3K4me3修饰剂在秀丽隐杆线虫的种系中作用，以触发脂肪代谢体细胞组织的变化，表明脂肪种系和躯体之间的非细胞自主信号传导代谢。使用高吞吐量质谱法，我们发现H3K4me3-甲基转移酶不足战争富含几种特定单单饱和脂肪酸（MUFA）：油酸，棕榈酸和顺式脂肪酸（MUFA）疫苗酸。这种脂肪代谢转换为MUFA需要一个配置的网络，涉及转录因素SPB-1/SREBP1，NHR-49/PPARα和Delta-9脂肪酸去饱和酶，以及内源性的 MUFA积累是寿命延长所必需的。有趣的是，饮食补充个人 MUFA足以在蠕虫中延长寿命。过量的脂肪储存与动脉粥样硬化和糖尿病等疾病有关，但是我们的数据建议脂肪组成至关重要，并且表观遗传重塑会导致特定的脂肪酸增加寿命。因为产生不饱和脂肪酸的基因在整个范围内高度构成进化，内源性或饮食中的MUFA可以促进人类的寿命。令人兴奋的新问题由这些观察结果是：MUFA代谢如何受到表观遗传变化和环境的影响刺激？种系和躯体组织之间的交流如何策划以影响脂肪作品？后代遗传的脂肪组成的变化是否以变革方式？和 MUFA如何延长寿命？秀丽隐杆线虫是脂肪代谢的绝佳模型遗传能力，因为饱和到不饱和脂肪酸的转化的机械完全是保守。该提案将检验以下假设：种系中H3K4me3的表观遗传变化启动一个信号，该信号诱导转向MUFA在特定的体细胞组织中的积累，从而导致寿命延长。将开发三个特定目标来测试这个新想法： 1。确定种系H3K4me3修饰剂如何导致父母和后代。 2。确定诱导转向单不饱和脂肪酸和寿命的分子机制对改变种系H3K4me3和环境刺激的反应。 3。表征促进寿命的特定脂肪酸的调节和作用方式。这些研究将提供对种系中特定脂肪代谢调节的机械见解，有可能发现新的信号分子，这些分子告知SOMA种系的代谢状态。此外，提出的实验将确定将表观遗传变化与脂肪联系起来的关键途径世代相传的代谢。最后，秀丽隐杆线虫中的这项工作将决定脂肪代谢如何能够拥有对HealthSpan和寿命的益处，并为测试MUFA的保守作用提供了基础其他物种的代谢。