Regulation of chromatin modifiers by metabolites of the Krebs cycle

三羧酸循环代谢物对染色质修饰剂的调节

• 批准号: RGPIN-2017-05227
• 负责人: Mallette, FrédérickAntoine
• 金额: $ 2.04万
• 依托单位: Université de Montréal
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2017
• 资助国家: 加拿大
• 起止时间: 2017-01-01 至 2018-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=629882
• 关键词: Regulation; chromatin; modifiers; metabolites; Krebs

In the nucleus of eukaryotic cells, the genome is tightly packed into chromatin, a complex arrangement of protein and DNA. The chromatin structure governs the establishment and maintenance of gene expression patterns, and is therefore determinant in several critical outcomes at the cellular levels, such as differentiation and genome stability. Interestingly, recent evidences have demonstrated that numerous chromatin modifiers are regulated by metabolites issued from mitochondria, a specialized energy-producing organelle in eukaryotic cells. We therefore anticipate that metabolism alterations results into chromatin modifications and gene expression changes. Our research aims to document extensively the molecular outcomes of metabolite unbalance at the level of chromatin, and to uncover metabolic-responsive gene pathways. The novelty of our research resides into an unbiased approach and extensive analysis of all possible modifications induced by metabolite alterations. We will make use of two complementary biological models, human cells and C.elegans, a classical model for in vivo studies. Ultimately we will contribute to our knowledge on a fascinating metabolism-epigenetics crosstalk.

在真核细胞的细胞核中，基因组被紧密地包装在染色质中，染色质是蛋白质和DNA的复杂排列。染色质结构控制着基因表达模式的建立和维持，因此在细胞水平上决定着几个关键结果，如分化和基因组稳定性。有趣的是，最近的证据表明，许多染色质修饰剂是由线粒体，在真核细胞中专门的能源生产细胞器发出的代谢产物的调节。因此，我们预期代谢改变导致染色质修饰和基因表达变化。我们的研究旨在广泛记录染色质水平代谢失衡的分子结果，并揭示代谢反应基因通路。我们研究的新奇在于一种无偏见的方法和对代谢物改变引起的所有可能的修饰的广泛分析。我们将利用两个互补的生物模型，人类细胞和秀丽隐杆线虫，一个经典的模型，在体内研究。最终，我们将有助于我们对一个迷人的代谢表观遗传学串扰的知识。