Transcription factors C/EBPβ and C/EBPδ are induced within hours after initiation of adipogenesis in culture. They directly promote the expression of master adipogenic transcription factors peroxisome proliferator-activated receptor γ (PPARγ) and C/EBPα and are required for adipogenesis in vivo. However, the mechanism that controls the induction of C/EBPβ and C/EBPδ remains elusive. We previously showed that histone methyltransferases MLL3/MLL4 and associated PTIP are required for the induction of PPARγ and C/EBPα during adipogenesis. Here, we show MLL3/MLL4/PTIP-associated protein PAGR1 (also known as PA1) cooperates with phosphorylated CREB and ligand-activated glucocorticoid receptor to directly control the induction of C/EBPβ and C/EBPδ in the early phase of adipogenesis. Deletion of Pagr1 in white and brown preadipocytes prevents the induction of C/EBPβ and C/EBPδ and leads to severe defects in adipogenesis. Adipogenesis defects in PAGR1-deficient cells can be rescued by the ectopic expression of C/EBPβ or PPARγ. Finally, the deletion of Pagr1 in Myf5⁺ precursor cells impairs brown adipose tissue and muscle development. Thus, by controlling the induction of C/EBPβ and C/EBPδ, PAGR1 plays a critical role in adipogenesis.

中文翻译：

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MLL3 / MLL4相关的PAGR1通过控制C /EBPβ和C /EBPδ的诱导来调节脂肪形成。

在培养物中脂肪生成开始后数小时内就诱导了转录因子C /EBPβ和C /EBPδ。它们直接促进主要的脂肪形成转录因子过氧化物酶体增殖物激活受体γ（PPARγ）和C /EBPα的表达，并且是体内脂肪形成所必需的。但是，控制C /EBPβ和C /EBPδ诱导的机制仍然难以捉摸。我们先前显示，在脂肪形成过程中，组蛋白甲基转移酶MLL3 / MLL4和相关的PTIP是诱导PPARγ和C /EBPα所必需的。在这里，我们显示了MLL3 / MLL4 / PTIP相关蛋白PAGR1（也称为PA1）与磷酸化CREB和配体激活的糖皮质激素受体协同作用，以直接控制脂肪形成的早期阶段C /EBPβ和C /EBPδ的诱导。Pagr1的删除在白色和棕色前脂肪细胞中，β-内啡肽可阻止C /EBPβ和C /EBPδ的诱导，并导致严重的脂肪形成缺陷。可以通过异位表达C /EBPβ或PPARγ来挽救PAGR1缺陷细胞的脂肪生成缺陷。最后，Myf5 ⁺前体细胞中Pagr1的缺失损害了棕色脂肪组织和肌肉的发育。因此，通过控制C /EBPβ和C /EBPδ的诱导，PAGR1在脂肪形成中起关键作用。