Brown adipose tissue(BAT)plays a key role in thermogenesis during acute cold exposure.However,it remains unclear how BAT is prepared to rapidly turn on thermogenic genes.Here,we show that damage-specific DNA binding p...Brown adipose tissue(BAT)plays a key role in thermogenesis during acute cold exposure.However,it remains unclear how BAT is prepared to rapidly turn on thermogenic genes.Here,we show that damage-specific DNA binding protein 1(DDB1)mediates the rapid transcription of thermogenic genes upon acute cold exposure.Adipose-or BAT-specific Ddb1 knockout mice show severely whitened BAT and significantly decreased expression of thermogenic genes.These mice develop hypothermia when subjected to acute cold exposure at 4℃ and partial lipodystrophy on a high-fat diet due to deficiency in fatty acid oxidation.Mechanistically,DDB1 binds the promoters of Ucp1 and Ppargc1a and recruits positive transcriptional elongation factor b(P-TEFb)to release promoter-proximally paused RNA polymerase II(Pol II),thereby enabling rapid and synchronized transcription of thermogenic genes upon acute cold exposure.Our findings have thus provided a regulatory mechanism of how BAT is prepared to respond to acute cold challenge.展开更多
基金This work was supported by the National Key R&D Program of China(2020YFA0803601)the National Natural Science Foundation of China(32125022 and 32101046)the China Postdoctoral Science Foundation(2019M661348 and 2020T130115).
文摘Brown adipose tissue(BAT)plays a key role in thermogenesis during acute cold exposure.However,it remains unclear how BAT is prepared to rapidly turn on thermogenic genes.Here,we show that damage-specific DNA binding protein 1(DDB1)mediates the rapid transcription of thermogenic genes upon acute cold exposure.Adipose-or BAT-specific Ddb1 knockout mice show severely whitened BAT and significantly decreased expression of thermogenic genes.These mice develop hypothermia when subjected to acute cold exposure at 4℃ and partial lipodystrophy on a high-fat diet due to deficiency in fatty acid oxidation.Mechanistically,DDB1 binds the promoters of Ucp1 and Ppargc1a and recruits positive transcriptional elongation factor b(P-TEFb)to release promoter-proximally paused RNA polymerase II(Pol II),thereby enabling rapid and synchronized transcription of thermogenic genes upon acute cold exposure.Our findings have thus provided a regulatory mechanism of how BAT is prepared to respond to acute cold challenge.
