TAF1 histone acetyltransferase activity in Sp1 activation of the cyclin D1 promoter
TAF1 histone acetyltransferase activity in Sp1 activation of the cyclin D1 promoter
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DOI：
10.1128/mcb.25.10.4321-4332.2005
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发表时间：
2005-05-01
影响因子：
5.3
通讯作者：
Wang, EH
中科院分区：
文献类型：
--
作者：
Hilton, TL;Li, Y;Wang, EH
TATA 结合蛋白相关因子 TAF1 的组蛋白乙酰转移酶 (HAT) 结构域内的错义突变会诱导 ts13 细胞经历 G 晚期停滞并减少细胞周期蛋白 D1 转录。我们发现HAT活性缺陷的TAF1突变体（Delta 844-850和Delta 848-850，其中氨基酸844至850和848至850分别被删除）无法弥补细胞增殖和细胞周期蛋白D1转录中的ts13缺陷。染色质免疫沉淀分析显示，在 ts13 细胞中 TAF1 失活后，细胞周期蛋白 D1 启动子处的组蛋白 H3 乙酰化减少，但 c-fos 启动子处的组蛋白 H3 乙酰化没有减少。细胞周期蛋白 D1 启动子处 H3 的低乙酰化可通过组蛋白脱乙酰酶抑制剂曲古抑菌素 A (TSA) 处理或通过表达保留 HAT 活性的 TAF1 蛋白来逆转。包含细胞周期蛋白 D1 和 c-fos 核心的 Sp1 位点的嵌合启动子的转录在 ts13 细胞中仍然依赖于 TAF1。 TSA 处理使细胞周期蛋白 D1-c-fos 嵌合体在 39.5 摄氏度下恢复了全部活性。体内基因组足迹实验表明，在 ts13 细胞中，细胞周期蛋白 D1 启动子 Sp1 位点上的蛋白质-DNA 相互作用在 39.5 摄氏度下受到损害。这些数据使我们推测 TAFI 依赖性组蛋白乙酰化促进转录因子与 Sp1 位点结合，从而激活细胞周期蛋白 D1 转录并最终从 G(1) 期进展到 S 期。
A missense mutation within the histone acetyltransferase (HAT) domain of the TATA binding protein-associated factor TAF1 induces ts13 cells to undergo a late G, arrest and decreases cyclin D1 transcription. We have found that TAF1 mutants (Delta 844-850 and Delta 848-850, from which amino acids 844 through 850 and 848 through 850 have been deleted, respectively) deficient in HAT activity are unable to complement the ts13 defect in cell proliferation and cyclin D1 transcription. Chromatin immunoprecipitation assays revealed that histone H3 acetylation was reduced at the cyclin D1 promoter but not the c-fos promoter upon inactivation of TAF1 in ts13 cells. The hypoacetylation of H3 at the cyclin D1 promoter was reversed by treatment with trichostatin A (TSA), a histone deacetylase inhibitor, or by expression of TAF1 proteins that retain HAT activity. Transcription of a chimeric promoter containing the Sp1 sites of cyclin D1 and c-fos core remained TAF1 dependent in ts13 cells. Treatment with TSA restored full activity to the cyclin D1-c-fos chimera at 39.5 degrees C. In vivo genomic footprinting experiments indicate that protein-DNA interactions at the Sp1 sites of the cyclin D1 promoter were compromised at 39.5 degrees C in ts13 cells. These data have led us to hypothesize that TAFI-dependent histone acetylation facilitates transcription factor binding to the Sp1 sites, thereby activating cyclin D1 transcription and ultimately G(1)-to-S-phase progression.