LSD1 Interacts with Zfp516 to Promote UCP1 Transcription and Brown Fat Program.
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.
Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA.
Audrey
A
Sambeat
Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA; Endocrinology Program, University of California, Berkeley, Berkeley, CA 94720, USA.
Olga
O
Gulyaeva
Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA; Comparative Biochemistry Program, University of California, Berkeley, Berkeley, CA 94720, USA.
Jon
J
Dempersmier
Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA.
Kevin M
KM
Tharp
Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA.
Andreas
A
Stahl
Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA.
Sarah M
SM
Paul
Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA; Endocrinology Program, University of California, Berkeley, Berkeley, CA 94720, USA; Comparative Biochemistry Program, University of California, Berkeley, Berkeley, CA 94720, USA. Electronic address: hsul@berkeley.edu.
Hei Sook
HS
Sul
D041721:3T3-L1 Cells; D052437:Adipocytes, Brown / Q000378:metabolism; D002001:Adipose Tissue, Brown / Q000254:growth & development / Q000378:metabolism*; D052436:Adipose Tissue, White / Q000378:metabolism; D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D003080:Cold Temperature; D057809:HEK293 Cells; D056466:Histone Demethylases / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D022722:Thermogenesis / Q000235:genetics; D015534:Trans-Activators / Q000378:metabolism*; D014158:Transcription, Genetic; D000071256:Uncoupling Protein 1 / Q000235:genetics*
D015534:Trans-Activators; D000071256:Uncoupling Protein 1; C000596710:Zfp516 protein, mouse; D056466:Histone Demethylases; C504076:KDM1a protein, mouse