Jeong Kyuho, Kwon Hayeong, Lee Jaewoong, Jang Donghwan, Pak Yunbae
Department of Biochemistry, Division of Applied Life Science (BK21 Plus Program), PMBBRC, Gyeongsang National University, Jinju 660-701, Korea.
Department of Biochemistry, Division of Applied Life Science (BK21 Plus Program), PMBBRC, Gyeongsang National University, Jinju 660-701, Korea
Nucleic Acids Res. 2015 Mar 31;43(6):3114-27. doi: 10.1093/nar/gkv181. Epub 2015 Mar 9.
Insulin controls transcription to sustain its physiologic effects for the organism to adapt to environmental changes added to genetic predisposition. Nevertheless, insulin-induced transcriptional regulation by epigenetic factors and in defined nuclear territory remains elusive. Here we show that inner nuclear membrane (INM)-integrated caveolin-2 (Cav-2) regulates insulin-response epigenetic activation of Egr-1 and JunB genes at the nuclear periphery. INM-targeted pY19-Cav-2 in response to insulin associates specifically with the A-type lamin, disengages the repressed Egr-1 and JunB promoters from lamin A/C through disassembly of H3K9me3, and facilitates assembly of H3K9ac, H3K18ac and H3K27ac by recruitment of GCN5 and p300 and the subsequent enrichment of RNA polymerase II (Pol II) on the promoters at the nuclear periphery. Our findings show that Cav-2 is an epigenetic regulator of histone H3 modifications, and provide novel mechanisms of insulin-response epigenetic activation at the nuclear periphery.
胰岛素控制转录以维持其生理效应，使机体在遗传易感性基础上适应环境变化。然而，胰岛素通过表观遗传因子以及在特定核区域诱导的转录调控仍不清楚。在此，我们表明，整合在内核膜（INM）上的小窝蛋白2（Cav-2）在核周边区域调节胰岛素反应性Egr-1和JunB基因的表观遗传激活。响应胰岛素时，靶向INM的pY19-Cav-2与A型核纤层蛋白特异性结合，通过H3K9me3的解离使被抑制的Egr-1和JunB启动子与核纤层蛋白A/C分离，并通过招募GCN5和p300以及随后RNA聚合酶II（Pol II）在核周边区域启动子上的富集，促进H3K9ac、H3K18ac和H3K27ac的组装。我们的研究结果表明，Cav-2是组蛋白H3修饰的表观遗传调节因子，并提供了核周边区域胰岛素反应性表观遗传激活的新机制。
