Molecular networks and epigenomic mechanisms underpinning white fat browning capacity

支持白色脂肪褐变能力的分子网络和表观基因组机制

• 批准号: 441904031
• 负责人: Professor Dr. Yongguo Li
• 金额: --
• 依托单位: Institut für Pharmakologie und Toxikologie
• 依托单位国家: 德国
• 项目类别: Independent Junior Research Groups
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/441904031?language=en
• 关键词: Molecular; networks; epigenomic; mechanisms; underpinning

Obesity develops when energy intake chronically exceeds energy expenditure. The capacity for thermogenic adipocytes (brown and brite/beige) to dissipate chemical energy therefore increasing energy expenditure offers great potential to combat obesity. With limited amount of human brown fat, increasing the relative abundance of brite cells in white fat (WAT browning) offers an opportunity to increase the mass of thermogenic brite adipose tissues and meanwhile decrease the amount of WAT, thereby turning an energy-storing organ into an energy-dissipating one. However, a comprehensive understanding of the regulatory mechanisms mediating WAT browning is still lacking. Variation in white fat browning propensity among inbred mouse strains provides a unique opportunity to zoom in on the core regulators of the browning program across different genotypes. In previous studies, combining comparative transcriptomics, perturbation-based assays and gene network analyses, I revealed novel regulators as well as a core regulatory network that contributes to brite adipogenesis. Although these results constitute the most comprehensive attempt to define the regulatory network underlying white fat browning, further efforts are needed to perform in-depth characterization of key factors, refine the organization of the network and draw a more complete canvas of the sources of gene expression variability in this system. Moreover, there is a more complex source of strain variation in browning propensity, exemplified by cis-driven between C57BL/6J and 129S6/SvEvTac, while trans-driven between C57BL/6J and FVB/NJ. My future work now aims at the systematic analyses of transcription factor binding, epigenetic state and gene expression to identify natural genetic variants that affect the browning capacity. Specifically, I hypothesize that distinct genetic variants affect DNA-binding of transcription factors, which lead to variable histone modifications and collectively influence gene expression and browning propensity (Objective A) and operating through highly connected cellular networks of genes targeting browning capacity (Objective B). Testing these hypotheses will lead to the discovery of novel functional regulatory elements, candidate genes, epigenetic basis and molecular networks underlying white fat browning. Combined with further extensive validation both in vitro and in vivo (Objective C) through gain- and loss-of-function experiments as well as simultaneous activation of multiple genes with the CRISPR–dCas9-activator system, an in-depth understanding of novel key transcription factor(s) as well as molecular networks in the control of browning capability will be obtained. Together, we aim to devise a comprehensive molecular network that regulates white fat browning. In the long run, a full understanding of the molecular architecture underlying brite cell recruitment could facilitate the development of therapeutic approaches for combating metabolic imbalance.

当能量摄入长期超过能量消耗时，肥胖就会发生。产热脂肪细胞（棕色和白色/米色）消耗化学能的能力，因此增加能量消耗，为对抗肥胖提供了巨大的潜力。由于人类棕色脂肪的数量有限，增加白色脂肪中白质细胞的相对丰度（WAT褐化）提供了增加产热白质脂肪组织质量的机会，同时减少WAT的数量，从而将能量储存器官转变为能量消耗器官。然而，对介导WAT褐变的调控机制仍缺乏全面的了解。在近亲繁殖的小鼠品系中，白色脂肪褐变倾向的变化提供了一个独特的机会，可以放大不同基因型中褐变程序的核心调节因子。在之前的研究中，我结合了比较转录组学、基于扰动的分析和基因网络分析，发现了新的调节因子以及一个有助于脂肪形成的核心调节网络。尽管这些结果构成了定义白色脂肪褐变的调控网络的最全面的尝试，但需要进一步的努力来深入表征关键因素，完善网络的组织，并绘制出该系统中基因表达变异性来源的更完整的画布。此外，菌株褐变倾向的变异来源更为复杂，C57BL/6J与129S6/SvEvTac为顺式驱动，而C57BL/6J与FVB/NJ为反式驱动。我未来的工作目标是系统分析转录因子结合、表观遗传状态和基因表达，以确定影响褐变能力的自然遗传变异。具体来说，我假设不同的遗传变异会影响转录因子的dna结合，从而导致可变的组蛋白修饰，并共同影响基因表达和褐变倾向（目标A），并通过靶向褐变能力的基因高度连接的细胞网络进行操作（目标B）。测试这些假设将导致发现新的功能调控元件，候选基因，表观遗传基础和分子网络背后的白色脂肪褐变。结合进一步广泛的体外和体内验证（目标C），通过获得和失去功能的实验，以及crispr - dcas9激活器系统同时激活多个基因，深入了解新的关键转录因子(s)和分子网络在褐变能力的控制。总之，我们的目标是设计一个全面的分子网络，调节白色脂肪褐变。从长远来看，充分了解白石细胞招募的分子结构可以促进对抗代谢失衡的治疗方法的发展。