Brown adipose tissue (BAT) is responsible for non-shivering thermogenesis, but it is absent in some mammals, including pigs. During development, BAT progenitors are derived from paired box 7 (Pax7)-expressing somitic mesodermal stem cells, which also give rise to skeletal muscle. However, the intrinsic mechanisms underlying the fate decisions between brown fat and muscle progenitors remain elusive. In this study, we analyzed the dynamics of chromatin landscape during the segregation of specification of brown fat and muscle lineages from Pax7⁺ progenitors, aiming to uncover epigenetic factors that drive BAT formation. Notably, myogenic progenitors were specified at embryonic day (E) 12.5, exhibiting high levels of H3K4me3 and low H3K27me3 at muscle-related genes. In contrast, the specification of the BAT lineage occurred much later, with coordinated step-wise depositions of histone modifications at BAT associated genes from E10.5 to E14.5. We identified the early B-cell factor 2 (EBF2) as a key driver of the progressive specification of brown fat lineage. Mechanistically, EBF2 interacts with transcriptional co-activators CREB binding protein/ E1A-binding protein p300 (CBP/P300) to induce chromatin acetylation at BAT-associated genes to promote brown adipogenesis. Both mouse and pig Ebf2 could potently stimulate adipogenesis in unspecified multipotent mesodermal stem cells. However, in pigs, EBF2 expression was depleted during the critical lineage specification time window, thus preventing the embryonic development of BAT. Hence, the elevation of EBF2 in mice, but not in pigs, promote chromatin activation to drive the progressive specification of brown fat lineage.

中文翻译：

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小鼠而非猪中 EBF2 升高通过染色质激活驱动进行性棕色脂肪谱系规范


棕色脂肪组织 （BAT） 负责非颤抖产热，但在一些哺乳动物（包括猪）中不存在。在发育过程中，BAT 祖细胞来源于表达配对盒 7 （Pax7） 的拟体中胚层干细胞，这些细胞也产生骨骼肌。然而，棕色脂肪和肌肉祖细胞之间命运决定的内在机制仍然难以捉摸。在这项研究中，我们分析了棕色脂肪和肌肉谱系与 Pax7 ⁺ 祖细胞分离过程中染色质景观的动力学，旨在揭示驱动 BAT 形成的表观遗传因素。值得注意的是，在胚胎第 （E） 12.5 天指定生肌祖细胞，在肌肉相关基因上表现出高水平的 H3K4me3 和低水平的 H3K27me3。相比之下，BAT 谱系的规范发生得要晚得多，从 E10.5 到 E14.5，组蛋白修饰在 BAT 相关基因上的协调逐步沉积。我们确定早期 B 细胞因子 2 （EBF2） 是棕色脂肪谱系进行性规范的关键驱动因素。从机制上讲，EBF2 与转录共激活因子 CREB 结合蛋白/E1A 结合蛋白 p300 （CBP/P300） 相互作用，诱导 BAT 相关基因的染色质乙酰化，从而促进棕色脂肪生成。小鼠和猪 Ebf2 均可有效刺激未指定的多能中胚层干细胞中的脂肪生成。然而，在猪中，EBF2 表达在关键谱系规格时间窗口内耗尽，从而阻止了 BAT 的胚胎发育。因此，小鼠中 EBF2 的升高，而不是猪中，促进染色质活化，以驱动棕色脂肪谱系的渐进性规范。