Systems-Genetics-Based Inference of a Core Regulatory Network Underlying White Fat Browning
Systems-Genetics-Based Inference of a Core Regulatory Network Underlying White Fat Browning
复制标题
DOI：
10.1016/j.celrep.2019.11.053
复制
发表时间：
2019-12-17
期刊：
影响因子：
8.8
通讯作者：
Klingenspor, Martin
中科院分区：
文献类型：
--
作者：
Li, Yongguo;Schwalie, Petra C.;Klingenspor, Martin
白色脂肪组织褐色化（WAT）是一种将能量储存器官转变为能量消耗器官的有效方法，因此在对抗肥胖方面可能具有治疗价值。然而，对介导WAT褐变的调控机制仍缺乏全面的了解。在这里，我们利用近亲繁殖小鼠品系之间WAT褐变倾向的巨大自然差异，以获得协调这一细胞过程的核心调控网络的包容性观点。结合比较转录组学、基于扰动的验证和基因网络分析，我们提出了腹沟WAT褐变的全面基因调控网络，揭示了多达四个不同的调控模块，这些模块在未发现的转录因子中起着关键作用，同时也为brite脂肪形成的遗传结构提供了深入的见解。因此，所提出的研究结果大大增加了我们对介导脂肪组织有趣的细胞异质性和可塑性的分子驱动因素的理解。
Recruitment of brite/beige cells, known as browning of white adipose tissue (WAT), is an efficient way to turn an energy-storing organ into an energy-dissipating one and may therefore be of therapeutic value in combating obesity. However, a comprehensive understanding of the regulatory mechanisms mediating WAT browning is still lacking. Here, we exploit the large natural variation in WAT browning propensity between inbred mouse strains to gain an inclusive view of the core regulatory network coordinating this cellular process. Combining comparative transcriptomics, perturbation-based validations, and gene network analyses, we present a comprehensive gene regulatory network of inguinal WAT browning, revealing up to four distinct regulatory modules with key roles for uncovered transcriptional factors, while also providing deep insights into the genetic architecture of brite adipogenesis. The presented findings therefore greatly increase our understanding of the molecular drivers mediating the intriguing cellular heterogeneity and plasticity of adipose tissue.