Sambeat Audrey, Gulyaeva Olga, Dempersmier Jon, Tharp Kevin M, Stahl Andreas, Paul Sarah M, Sul Hei Sook
Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA.
Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA; Endocrinology Program, University of California, Berkeley, Berkeley, CA 94720, USA.
Cell Rep. 2016 Jun 14;15(11):2536-49. doi: 10.1016/j.celrep.2016.05.019. Epub 2016 Jun 2.
Zfp516, a brown fat (BAT)-enriched and cold-inducible transcription factor, promotes transcription of UCP1 and other BAT-enriched genes for non-shivering thermogenesis. Here, we identify lysine-specific demethylase 1 (LSD1) as a direct binding partner of Zfp516. We show that, through interaction with Zfp516, LSD1 is recruited to UCP1 and other BAT-enriched genes, such as PGC1α, to function as a coactivator by demethylating H3K9. We also show that LSD1 is induced during brown adipogenesis and that LSD1 and its demethylase activity is required for the BAT program. Furthermore, we show that LSD1 ablation in mice using Myf5-Cre alters embryonic BAT development. Moreover, BAT-specific deletion of LSD1 via the use of UCP1-Cre impairs the BAT program and BAT development, making BAT resemble WAT, reducing thermogenic activity and promoting obesity. Finally, we demonstrate an in vivo requirement of the Zfp516-LSD1 interaction for LSD1 function in BAT gene activation.
锌指蛋白516（Zfp516）是一种在棕色脂肪（BAT）中高度富集且受寒冷诱导的转录因子，可促进解偶联蛋白1（UCP1）及其他BAT富集基因的转录，以实现非颤抖性产热。在此，我们鉴定出赖氨酸特异性去甲基化酶1（LSD1）是Zfp516的直接结合伴侣。我们发现，通过与Zfp516相互作用，LSD1被招募至UCP1及其他BAT富集基因（如PGC1α），通过使组蛋白H3第9位赖氨酸去甲基化来发挥共激活因子的作用。我们还表明，LSD1在棕色脂肪生成过程中被诱导，且BAT程序需要LSD1及其去甲基化酶活性。此外，我们发现利用Myf5-Cre在小鼠中敲除LSD1会改变胚胎期BAT的发育。而且，通过使用UCP1-Cre在BAT中特异性敲除LSD1会损害BAT程序和BAT发育，使BAT类似于白色脂肪组织（WAT），降低产热活性并促进肥胖。最后，我们证明了在体内BAT基因激活过程中，Zfp516-LSD1相互作用对于LSD1发挥功能是必需的。
