Hop2 interacts with the transcription factor CEBPα and suppresses adipocyte differentiation.
Hop2 interacts with the transcription factor CEBPα and suppresses adipocyte differentiation.
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DOI：
10.1016/j.jbc.2021.101264
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发表时间：
2021-11
期刊：
影响因子：
--
通讯作者：
Yang X
中科院分区：
文献类型：
--
作者：
Lin T;Zhang Y;Zhang T;Steckler RA;Yang X
CCAAT增强子结合蛋白(CEBP)转录因子(TF)是已知的促进脂肪细胞分化的转录因子；然而，CEBP转录因子的抑制因子到目前为止还没有报道。在这里，我们发现同源染色体配对蛋白2(Hop2)作为TFCEBPα的抑制因子。我们发现，Hop2基因在脂肪组织中高度特异地表达，DNA转染显示，异位表达的Hop2抑制了CEBP诱导的报告基因活性。免疫下拉实验和免疫共沉淀实验表明，重组和异位表达的Hop2与CEBPα相互作用；免疫荧光和免疫共沉淀法观察到内源性Hop2和CEBPα在3T3前脂肪细胞和脂肪细胞的胞核内相互作用。此外，在3T3前脂肪细胞中稳定过表达Hop2抑制了脂肪细胞的分化和脂肪细胞标志基因的表达。这些体外数据表明，Hop2通过抑制CEBP介导的反式激活来抑制脂肪生成。与霍普2在脂肪形成中的负面作用一致，去除霍普2(Hop2−/−)导致小鼠体重、脂肪体积、脂肪细胞大小和成脂标记基因表达增加。分离的脂肪间充质干细胞成脂分化实验显示，在Hop2−/−脂肪间充质干细胞培养中形成的含有脂滴的集落数量多于对照组，这与成脂标记基因的表达增加有关。最后，染色质免疫沉淀显示内源性CEBPα与过氧化物酶体增殖物激活受体γ、主要的成脂因子和已知的CEBPα靶基因有较高的结合活性。因此，我们的研究首次确定Hop2是CEBPα的内在抑制因子，从而抑制脂肪细胞的成脂作用。
CCAAT enhancer binding protein (CEBP) transcription factors (TFs) are known to promote adipocyte differentiation; however, suppressors of CEBP TFs have not been reported thus far. Here, we find that homologous chromosome pairing protein 2 (Hop2) functions as an inhibitor for the TF CEBPα. We found that Hop2 mRNA is highly and specifically expressed in adipose tissue, and that ectopic Hop2 expression suppresses reporter activity induced by CEBP as revealed by DNA transfection. Recombinant and ectopically expressed Hop2 was shown to interact with CEBPα in pull-down and coimmunoprecipitation assays, and interaction between endogenous Hop2 and CEBPα was observed in the nuclei of 3T3 preadipocytes and adipocytes by immunofluorescence and coimmunoprecipitation of nuclear extracts. In addition, Hop2 stable overexpression in 3T3 preadipocytes inhibited adipocyte differentiation and adipocyte marker gene expression. These in vitro data suggest that Hop2 inhibits adipogenesis by suppressing CEBP-mediated transactivation. Consistent with a negative role for Hop2 in adipogenesis, ablation of Hop2 (Hop2−/−) in mice led to increased body weight, adipose volume, adipocyte size, and adipogenic marker gene expression. Adipogenic differentiation of isolated adipose-derived mesenchymal stem cells showed a greater number of lipid droplet–containing colonies formed in Hop2−/− adipose-derived mesenchymal stem cell cultures than in wt controls, which is associated with the increased expression of adipogenic marker genes. Finally, chromatin immunoprecipitation revealed a higher binding activity of endogenous CEBPα to peroxisome proliferator–activated receptor γ, a master adipogenic TF, and a known CEBPα target gene. Therefore, our study identifies for the first time that Hop2 is an intrinsic suppressor of CEBPα and thus adipogenesis in adipocytes.
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