Wang Guo-Li, Salisbury Elizabeth, Shi Xiurong, Timchenko Lubov, Medrano Estela E, Timchenko Nikolai A
Huffington Center on Aging and Department of Pathology, Baylor College of Medicine, Houston, Texas 77030, USA.
J Biol Chem. 2008 Sep 19;283(38):26169-78. doi: 10.1074/jbc.M803544200. Epub 2008 Jul 11.
Epigenetic control of liver proliferation involves cooperation between transcription factors and chromatin-remodeling proteins. In this work, we found that the levels of HDAC1 (histone deacetylase 1) are increased in quiescent livers of old mice. The elevation of HDAC1 in liver is mediated by the RNA-binding protein CUGBP1. We found that the age-associated CUGBP1-eIF2 complex binds to the 5' region of HDAC1 mRNA and increases translation of HDAC1 in the liver. Further analyses showed that CUGBP1 also increases expression of HDAC1 in cultured cells, in the livers of CUGBP1 transgenic mice, and in the livers of mice injected with cyclin D3, which enhances the formation of the CUGBP1-eIF2 complex. In livers of old mice, HDAC1 interacts with the transcription factor C/EBPalpha and is recruited by this protein to E2F-dependent promoters as a component of high M(r) C/EBPalpha-Brm complexes. The recruitment of HDAC1 to c-Myc and FoxM1B promoters leads to deacetylation of histone H3 at Lys-9 on these E2F-dependent promoters. We show that HDAC1 is an important mediator of growth-inhibitory activity of C/EBPalpha and that small interfering RNA-mediated inhibition of HDAC1 reduces the ability of C/EBPalpha to inhibit cell proliferation. In addition, we have found that both elevation of HDAC1 and interaction of C/EBPalpha with HDAC1 are controlled by cyclin D3-dependent mechanisms. Treatment of old mice with growth hormone, which reduces cyclin D3 levels, leads to the reduction of the CUGBP1-eIF2 complex, normalization of HDAC1 levels, and inhibition of interactions of HDAC1 with C/EBPalpha-Brm complexes. Thus, our data demonstrate that translational elevation of HDAC1 in livers of old mice is involved in the assembly of high M(r) protein-protein complexes that inhibit liver proliferation.
肝脏增殖的表观遗传控制涉及转录因子与染色质重塑蛋白之间的协同作用。在本研究中，我们发现老年小鼠静止肝脏中HDAC1（组蛋白去乙酰化酶1）水平升高。肝脏中HDAC1的升高由RNA结合蛋白CUGBP1介导。我们发现与年龄相关的CUGBP1-eIF2复合物结合到HDAC1 mRNA的5'区域并增加肝脏中HDAC1的翻译。进一步分析表明，CUGBP1还可增加培养细胞、CUGBP1转基因小鼠肝脏以及注射细胞周期蛋白D3的小鼠肝脏中HDAC1的表达，细胞周期蛋白D3可增强CUGBP1-eIF2复合物的形成。在老年小鼠肝脏中，HDAC1与转录因子C/EBPα相互作用，并作为高分子量C/EBPα-Brm复合物的一个组分被该蛋白招募至E2F依赖的启动子。HDAC1被招募至c-Myc和FoxM1B启动子导致这些E2F依赖启动子上组蛋白H3赖氨酸9位的去乙酰化。我们表明HDAC1是C/EBPα生长抑制活性的重要介质，并且小干扰RNA介导的HDAC1抑制降低了C/EBPα抑制细胞增殖的能力。此外，我们发现HDAC1的升高以及C/EBPα与HDAC1的相互作用均受细胞周期蛋白D3依赖机制的控制。用生长激素处理老年小鼠可降低细胞周期蛋白D3水平，导致CUGBP1-eIF2复合物减少、HDAC1水平正常化，并抑制HDAC1与C/EBPα-Brm复合物的相互作用。因此，我们的数据表明老年小鼠肝脏中HDAC1的翻译升高参与了抑制肝脏增殖的高分子量蛋白质-蛋白质复合物的组装。
