GSE122746
BCL6 reinforces brown adipocyte cellular identity to preserve thermogenic fitness
Brown adipose tissue (BAT) generates heat via uncoupled respiration, providing mammals with an evolutionary defense against environmental cold. Although the molecular pathways by which cold activates brown adipocytes are well understood, little is known about how BAT maintains its thermogenic capacity during adaptation to environmental warmth. Here, we identify the transcriptional repressor BCL6 as the switch for maintaining brown adipocyte cellular identity under warm conditions. Mice lacking BCL6 in their brown adipocytes display normal thermogenic responses when housed in a cool environment, but fail to maintain thermogenic fitness when housed under warm conditions. In a temperature-dependent manner, BCL6 suppresses apoptosis, fatty acid storage, and coupled respiration to maintain thermogenic competence in brown adipocytes. Enhancer analysis revealed that BCL6 reinforces brown-specific while opposing white-specific enhancers to maintain cellular identity. Thus, unlike other regulators, BCL6 is dispensable for differentiation and activation of brown adipocytes, but specifically required for their maintenance in warmth. Overall design: The temperature-dependent regulation of the mouse brown adipocyte transcriptome and epigenome by BCL6 was studied via RNA-Seq and H3K27ac ChIP-Seq in brown adipose tissue isolated from Ucp1-Cre BCL6-floxed mice housed at different temperatures. The BCL6 cistrome in mouse brown adipocytes was studied via BCL6 ChIP-Seq in brown adipose tissue isolated from Ucp1-Cre BCL6-floxed mice housed at 30 deg. C.