Qiu Yi, Zhao Yingming, Becker Matthias, John Sam, Parekh Bhavin S, Huang Suming, Hendarwanto Anindya, Martinez Elisabeth D, Chen Yue, Lu Hanxin, Adkins Nicholas L, Stavreva Diana A, Wiench Malgorzata, Georgel Philippe T, Schiltz R Louis, Hager Gordon L
Laboratory of Receptor Biology and Gene Expression, National Cancer Institute, National Institutes of Health, Building 41, B602, Bethesda, Maryland 20892, USA.
Mol Cell. 2006 Jun 9;22(5):669-79. doi: 10.1016/j.molcel.2006.04.019.
Although histone deacetylases (HDACs) are generally viewed as corepressors, we show that HDAC1 serves as a coactivator for the glucocorticoid receptor (GR). Furthermore, a subfraction of cellular HDAC1 is acetylated after association with the GR, and this acetylation event correlates with a decrease in promoter activity. HDAC1 in repressed chromatin is highly acetylated, while the deacetylase found on transcriptionally active chromatin manifests a low level of acetylation. Acetylation of purified HDAC1 inactivates its deacetylase activity, and mutation of the critical acetylation sites abrogates HDAC1 function in vivo. We propose that hormone activation of the receptor leads to progressive acetylation of HDAC1 in vivo, which in turn inhibits the deacetylase activity of the enzyme and prevents a deacetylation event that is required for promoter activation. These findings indicate that HDAC1 is required for the induction of some genes by the GR, and this activator function is dynamically modulated by acetylation.
尽管组蛋白去乙酰化酶（HDACs）通常被视为共抑制因子，但我们发现HDAC1可作为糖皮质激素受体（GR）的共激活因子。此外，细胞中的一部分HDAC1在与GR结合后会发生乙酰化，且这种乙酰化事件与启动子活性降低相关。处于抑制状态染色质中的HDAC1高度乙酰化，而在转录活跃染色质上发现的去乙酰化酶则表现出低水平的乙酰化。纯化的HDAC1乙酰化会使其去乙酰化酶活性失活，关键乙酰化位点的突变会消除HDAC1在体内的功能。我们提出，受体的激素激活会导致体内HDAC1逐渐乙酰化，进而抑制该酶的去乙酰化酶活性，并阻止启动子激活所需的去乙酰化事件。这些发现表明，HDAC1是GR诱导某些基因所必需的，且这种激活功能会受到乙酰化的动态调节。
