MLL3/MLL4-Associated PAGR1 Regulates Adipogenesis by Controlling Induction of C/EBPI3 and C/EBPS
MLL3/MLL4-Associated PAGR1 Regulates Adipogenesis by Controlling Induction of C/EBPI3 and C/EBPS
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DOI：
10.1128/mcb.00209-20
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发表时间：
2020-09-01
影响因子：
5.3
通讯作者：
Ge, Kai
中科院分区：
文献类型：
--
作者：
Lee, Ji-Eun;Cho, Young-Wook;Ge, Kai
转录因子C/EBP β和C/EBP β在培养物中脂肪形成启动后数小时内被诱导。它们直接促进主脂肪形成转录因子过氧化物酶体增殖物激活受体γ（PPAR γ）和C/EBP α的表达，并且是体内脂肪形成所需的。然而，控制C/EBP β和C/EBP δ诱导的机制仍然难以捉摸。我们以前的研究表明，组蛋白甲基转移酶MLL 3/MLL 4和相关的PTIP是在脂肪形成过程中诱导PPAR γ和C/EBP α所必需的。在此，我们发现MLL 3/MLL 4/PTIP相关蛋白PAGR 1（也称为PA 1）与磷酸化CREB和配体激活的糖皮质激素受体合作，在脂肪形成的早期阶段直接控制C/EBP β和C/EBP δ的诱导。白色和棕色前脂肪细胞中Pagr 1的缺失阻止了C/EBP β和C/EBP δ的诱导，并导致脂肪生成的严重缺陷。PAGR 1缺陷细胞中的脂肪生成缺陷可以通过C/EBP β或PPAR γ的异位表达来挽救。最后，Myf 5（+）前体细胞中Pagr 1的缺失会损害棕色脂肪组织和肌肉发育。因此，通过控制C/EBP β和C/EBP δ的诱导，PAGR 1在脂肪形成中起关键作用。
Transcription factors C/EBP beta and C/EBP beta are induced within hours after ini-tiation of adipogenesis in culture. They directly promote the expression of master adipo-genic transcription factors peroxisome proliferator-activated receptor gamma (PPAR gamma) and C/EBP alpha and are required for adipogenesis in vivo. However, the mechanism that controls the induction of C/EBP beta and C/EBP delta remains elusive. We previously showed that histone methyltransferases MLL3/MLL4 and associated PTIP are required for the induction of PPAR gamma and C/EBP alpha during adipogenesis. Here, we show MLL3/MLL4/PTIP-associated pro-tein PAGR1 (also known as PA1) cooperates with phosphorylated CREB and ligand-activated glucocorticoid receptor to directly control the induction of C/EBP beta and C/EBP delta in the early phase of adipogenesis. Deletion of Pagr1 in white and brown preadipocytes prevents the induction of C/EBP beta and C/EBP delta and leads to severe defects in adipogene-sis. Adipogenesis defects in PAGR1-deficient cells can be rescued by the ectopic expression of C/EBP beta or PPAR gamma. Finally, the deletion of Pagr1 in Myf5(+) precursor cells impairs brown adipose tissue and muscle development. Thus, by controlling the induction of C/EBP beta and C/EBP delta, PAGR1 plays a critical role in adipogenesis.