Life Sciences Institute and Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI, 48109, USA.
Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, 48109, USA.
Nat Commun. 2020 May 13;11(1):2379. doi: 10.1038/s41467-020-16148-1.
Brown and beige fat share a remarkably similar transcriptional program that supports fuel oxidation and thermogenesis. The chromatin-remodeling machinery that governs genome accessibility and renders adipocytes poised for thermogenic activation remains elusive. Here we show that BAF60a, a subunit of the SWI/SNF chromatin-remodeling complexes, serves an indispensable role in cold-induced thermogenesis in brown fat. BAF60a maintains chromatin accessibility at PPARγ and EBF2 binding sites for key thermogenic genes. Surprisingly, fat-specific BAF60a inactivation triggers more pronounced cold-induced browning of inguinal white adipose tissue that is linked to induction of MC2R, a receptor for the pituitary hormone ACTH. Elevated MC2R expression sensitizes adipocytes and BAF60a-deficient adipose tissue to thermogenic activation in response to ACTH stimulation. These observations reveal an unexpected dichotomous role of BAF60a-mediated chromatin remodeling in transcriptional control of brown and beige gene programs and illustrate a pituitary-adipose signaling axis in the control of thermogenesis.
棕色脂肪和米色脂肪具有惊人相似的转录程序，支持燃料氧化和产热。调控基因组可及性并使脂肪细胞准备好产热激活的染色质重塑机制仍然难以捉摸。在这里，我们表明，SWI/SNF 染色质重塑复合物的一个亚基 BAF60a 在棕色脂肪的冷诱导产热中起着不可或缺的作用。BAF60a 维持着关键产热基因中 PPARγ 和 EBF2 结合位点的染色质可及性。令人惊讶的是，脂肪特异性的 BAF60a 失活会引发更明显的冷诱导腹股沟白色脂肪组织的褐色化，这与垂体激素 ACTH 的受体 MC2R 的诱导有关。升高的 MC2R 表达使脂肪细胞和缺乏 BAF60a 的脂肪组织对 ACTH 刺激的产热激活敏感。这些观察结果揭示了 BAF60a 介导的染色质重塑在棕色和米色基因程序的转录控制中的意外二分角色，并说明了垂体-脂肪信号轴在产热控制中的作用。
