Laboratory of Systems Biology and Genetics, Institute of Bioengineering, School of Life Sciences, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.
Mol Cell. 2012 May 11;46(3):335-50. doi: 10.1016/j.molcel.2012.03.017. Epub 2012 Apr 19.
The molecular role of corepressors is poorly understood. Here, we studied the transcriptional function of the corepressor SMRT during terminal adipogenesis. Genome-wide DNA-binding profiling revealed that this corepressor is predominantly located in active chromatin regions and that most distal SMRT binding events are lost after differentiation induction. Promoter-proximal tethering of SMRT in preadipocytes is primarily mediated by KAISO through the conserved TCTCGCGAGA motif. Further characterization revealed that KAISO, similar to SMRT, accelerates the cell cycle and increases fat accumulation upon knockdown, identifying KAISO as an adipogenic repressor that likely modulates the mitotic clonal expansion phase of this process. SMRT-bound promoter-distal sites tend to overlap with C/EBPβ-bound regions, which become occupied by proadipogenic transcription factors after SMRT clearance. This reveals a role for SMRT in masking enhancers from proadipogenic factors in preadipocytes. Finally, we identified SMRT as an adipogenic gatekeeper as it directly fine-tunes transcription of pro- and antiadipogenic genes.
核心抑制物的分子作用尚不清楚。在这里，我们研究了核心抑制物 SMRT 在脂肪细胞终末分化过程中的转录功能。全基因组 DNA 结合谱分析显示，这种核心抑制物主要位于活性染色质区域，并且大多数远端 SMRT 结合事件在分化诱导后丢失。在脂肪前体细胞中，SMRT 的启动子近端连接主要通过 KAISO 通过保守的 TCTCGCGAGA 基序介导。进一步的表征表明，KAISO 类似于 SMRT，可在敲低后加速细胞周期并增加脂肪积累，表明 KAISO 是一种脂肪生成抑制剂，可能调节该过程的有丝分裂克隆扩增阶段。SMRT 结合的启动子远端位点往往与 C/EBPβ 结合区域重叠，在 SMRT 清除后，这些区域被前脂肪生成转录因子占据。这揭示了 SMRT 在脂肪前体细胞中掩蔽前脂肪生成因子的增强子的作用。最后，我们确定 SMRT 是一种脂肪生成的守门员，因为它直接微调促脂肪生成和抗脂肪生成基因的转录。
