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. 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.棕色脂肪组织（Brown Adipose Tissue，BAT）通过解偶联呼吸（uncoupled respiration）产热，为哺乳动物提供了抵御环境寒冷的进化防御策略。尽管寒冷激活棕色脂肪细胞的分子通路已被充分阐明，但学界对BAT在适应环境温热过程中维持产热能力的机制仍知之甚少。本研究鉴定出转录抑制因子（transcriptional repressor）BCL6是温热条件下维持棕色脂肪细胞身份的关键调控开关。在棕色脂肪细胞中特异性缺失BCL6的小鼠，在寒冷环境中可表现出正常的产热反应，但在温热环境中无法维持产热适配性。BCL6以温度依赖的方式抑制细胞凋亡（apoptosis）、脂肪酸储存及偶联呼吸（coupled respiration），以此维持棕色脂肪细胞的产热功能。增强子（enhancer）分析结果显示，BCL6可强化棕色脂肪细胞特异性增强子并拮抗白色脂肪细胞特异性增强子，从而稳定细胞身份。与其他调控因子不同，BCL6并非棕色脂肪细胞分化与激活的必需因子，而是其在温热环境中维持细胞状态的特异性必需调控因子。本研究针对饲养于不同温度环境下的Ucp1-Cre BCL6条件性敲除小鼠（Ucp1-Cre BCL6-floxed mice）分离的棕色脂肪组织，通过RNA测序（RNA-Seq）及H3K27ac染色质免疫共沉淀测序（H3K27ac ChIP-Seq），解析了BCL6对小鼠棕色脂肪细胞转录组与表观基因组的温度依赖性调控作用。此外，本研究通过对饲养于30℃环境下的上述基因工程小鼠分离的棕色脂肪组织进行BCL6染色质免疫共沉淀测序（BCL6 ChIP-Seq），解析了小鼠棕色脂肪细胞内的BCL6全基因组结合位点组（cistrome）。