Dangond F, Hafler D A, Tong J K, Randall J, Kojima R, Utku N, Gullans S R
Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
Biochem Biophys Res Commun. 1998 Jan 26;242(3):648-52. doi: 10.1006/bbrc.1997.8033.
The nucleosomal histones can be modified through reversible acetylation by histone acetyltransferases (HATs) and deacetylases (HDACs). HATs induce nucleosomal relaxation and allow DNA-binding by transcriptional activators. HDACs from corepressor complexes which negatively regulate cell growth. However, the HDAC inhibitors butyrate and Trichostatin A block T cell proliferation, suggesting that not all effects of HDACs lead to repression. Using mRNA differential display and 5'RACE we isolated human HDAC3, a novel gene that is upregulated in PHA-activated T cell clones. HDAC3 is homologous to other human HDACs and yeast RPD3. In peripheral blood mononuclear cells (PBMCs), activation by PHA, PMA and alpha-CD3 increased HDAC mRNA but no effect was seen with IFN-gamma, LPS, or IL-4. In contrast, GMCSF downregulated PBMC levels of HDAC3 mRNA. All HDACs were found to be ubiquitously expressed in immune and non-immune tissues. In human myeloid leukemia THP-1 cells, HDAC3 transfection resulted in increased size, aberrant nuclear morphology and cell cycle G2/M cell accumulation. Functional activity of the expressed HDAC3 protein was confirmed in alpha-HDAC3 antibody immunoprecipitates by a histone deacetylase assay. Our study suggests the participation of HDACs in cell cycle progression and activation.
核小体组蛋白可通过组蛋白乙酰转移酶（HATs）和去乙酰化酶（HDACs）进行可逆性乙酰化修饰。HATs可诱导核小体松弛，并使转录激活因子与DNA结合。来自共抑制复合物的HDACs对细胞生长起负向调节作用。然而，HDAC抑制剂丁酸盐和曲古抑菌素A可阻断T细胞增殖，这表明并非HDACs的所有作用都会导致抑制。我们利用mRNA差异显示和5'RACE技术分离出了人类HDAC3，这是一个在PHA激活的T细胞克隆中上调的新基因。HDAC3与其他人类HDACs以及酵母RPD3同源。在外周血单个核细胞（PBMCs）中，PHA、PMA和α-CD3激活可增加HDAC mRNA水平，但IFN-γ、LPS或IL-4无此作用。相反，GMCSF可下调PBMC中HDAC3 mRNA的水平。所有HDACs在免疫和非免疫组织中均有广泛表达。在人类髓系白血病THP-1细胞中，HDAC3转染导致细胞体积增大、核形态异常以及细胞周期G2/M期细胞积累。通过组蛋白去乙酰化酶检测，在α-HDAC3抗体免疫沉淀中证实了所表达的HDAC3蛋白的功能活性。我们的研究提示HDACs参与细胞周期进程和激活过程。
