Activation of the mouse histone deacetylase 1 gene by cooperative histone phosphorylation and acetylation
Activation of the mouse histone deacetylase 1 gene by cooperative histone phosphorylation and acetylation
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DOI：
10.1128/mcb.22.22.7820-7830.2002
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发表时间：
2002-11-01
影响因子：
5.3
通讯作者：
Seiser, C
中科院分区：
文献类型：
--
作者：
Hauser, C;Schuettengruber, B;Seiser, C
组蛋白去乙酰化酶1 （HDAC1）是染色质结构和基因表达的主要调节因子。严格控制HDAC1的表达对哺乳动物细胞的正常细胞周期进程至关重要。HDAC1 mRNA水平受生长因子和细胞内去乙酰化酶活性水平变化的调节。用大霉素或生长因子刺激丝裂原激活的蛋白激酶级联，同时用trichostatin A （TSA）抑制去乙酰化酶，导致稳定的组蛋白H3磷酸化乙酰化，并强烈诱导HDAC1表达。相比之下，单用异霉素激活核小体反应只导致组蛋白H3的短暂磷酸化乙酰化，而不影响HDAC1 mRNA水平。大霉素和TSA对HDAC1基因的转录诱导被H89有效阻断，H89是核小体反应的抑制剂。对组蛋白乙酰化和磷酸化动力学的详细研究表明，这两种修饰是协同作用的，是诱导HDAC1转录所必需的。大霉素与TSA或生长因子对HDAC1基因的激活伴随着HDAC1启动子相关组蛋白H3的磷酸化乙酰化。我们的研究结果为精确的调控机制提供了证据，该机制允许诱导HDAC1基因响应增殖信号并调节依赖于细胞内去乙酰化酶水平的HDAC1表达。
Histone deacetylase 1 (HDAC1) is a major regulator of chromatin structure and gene expression. Tight control of HDAC1 expression is essential for normal cell cycle progression of mammalian cells. HDAC1 mRNA levels are regulated by growth factors and by changes in intracellular deacetylase activity levels. Stimulation of the mitogen-activated protein kinase cascade by anisomycin or growth factors, together with inhibition of deacetylases by trichostatin A (TSA), leads to stable histone H3 phosphoacetylation and strongly induced HDAC1 expression. In contrast, activation of the nucleosomal response by anisomycin alone results only in transient phosphoacetylation of histone H3 without affecting HDAC1 mRNA levels. The transcriptional induction of the HDAC1 gene by anisomycin and TSA is efficiently blocked by H89, an inhibitor of the nucleosomal response. Detailed studies of the kinetics of histone acetylation and phosphorylation show that the two modifications are synergistic and essential for induced HDAC1 transcription. Activation of the HDAC1 gene by anisomycin together with TSA or by growth factors is accompanied by phosphoacetylation of HDAC1 promoter-associated histone H3. Our results present evidence for a precise regulatory mechanism which allows induction of the HDAC1 gene in response to proliferation signals and modulation of HDAC1 expression dependent on intracellular deacetylase levels.