Link between epigenetic modifiers and fat metabolism for healthy aging

项目总结 染色质修饰剂通过表观遗传变化将环境刺激整合到生理输出中，这可以 经久不衰，甚至超越世代。染色质重塑被发现可以延长人的寿命 几种生物，但染色质修饰剂如何延长寿命尚不清楚。我们已经做出了诱人的 观察到COMPASS甲基转移酶复合体的缺陷，它使组蛋白H3三甲基化 赖氨酸4(H3K4me3)，导致线虫寿命延长，这与脂肪变化有关 新陈代谢。有趣的是，H3K4me3修饰物在线虫的种系中作用于触发脂肪代谢 体细胞组织的变化，表明生殖系和胞体之间存在非细胞自主的脂肪信号 新陈代谢。利用高通量质谱仪，我们发现了H3K4me3-甲基转移酶缺陷蠕虫 富含几种特定的单不饱和脂肪酸(MUFAs)：油酸、棕榈油酸和顺式不饱和脂肪酸。 牛痘疫苗酸。这种脂肪代谢向MUFAs的转换需要一个涉及转录的保守网络 因子Spb-1/SREBP1，NHR-49/PPARα，和Delta-9脂肪酸去饱和酶，显著内源性 多不饱和脂肪酸的积累是延长寿命所必需的。有趣的是，个人的膳食补充 多不饱和脂肪酸足以延长蠕虫的寿命。 过多的脂肪储存与动脉粥样硬化和糖尿病等疾病有关，但我们的数据 这表明脂肪组成是至关重要的，表观遗传重塑可以导致特定的脂肪酸 延长寿命。因为产生不饱和脂肪酸的基因自始至终都高度保守 进化、内源性或饮食中的MUFA可以延长人类的寿命。提出了令人兴奋的新问题 这些观察是：表观遗传变化和环境如何影响MUFA新陈代谢 刺激？生殖系和体细胞组织之间的沟通是如何影响脂肪的？ 构图？脂肪成分的变化是否在后代中以跨代的方式遗传？和 MUFA如何起到延长寿命的作用？线虫是研究脂肪代谢的优秀模型，因为它具有 因为将饱和脂肪酸转化为不饱和脂肪酸的机制完全是 保守的。这一提议将检验这一假设，即生殖系中H3K4me3的表观遗传变化 启动一种信号，诱导切换到MUFA在特定的体细胞组织中积累，导致 延长寿命。 将制定三个具体目标来测试这一新想法： 1.确定胚系H3K4me3修饰剂如何导致亲本体脂成分的变化和 后代。 2.确定诱导人类向单不饱和脂肪酸转变和长寿的分子机制 对改变的生殖系H3K4me3和环境刺激的反应。 3.研究特定脂肪酸对延年益寿的调节作用和作用方式。 这些研究将从机制上深入了解生殖系和 可能会发现新的信号分子，告知细胞体生殖系的代谢状态。 此外，拟议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。 代际新陈代谢。最后，这项在线虫身上的研究将确定脂肪代谢如何 有益于健康和寿命，并为检验MUFA的保守作用提供了基础 其他物种的新陈代谢。

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.