LSD1 Interacts with Zfp516 to Promote UCP1 Transcription and Brown Fat Program

•Zfp516 recruits LSD1 at the UCP1 promoter, where it demethylates H3K9•LSD1 cooperates with Zfp516 to activate BAT genes and to promote thermogenesis•LSD1 ablation in brown adipose precursors impairs embryonic development of BAT•LSD1 ablation prevents browning of subcutaneous WAT induced by Zfp516

SummaryZfp516, 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.

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