Ho A K, Price D M, Dukewich W G, Steinberg N, Arnason T G, Chik C L
Department of Physiology, 7-26 Medical Sciences Building, Edmonton, Alberta, Canada.
Endocrinology. 2007 Oct;148(10):4592-600. doi: 10.1210/en.2007-0578. Epub 2007 Jul 12.
In this study we investigated the effect of histone acetylation on the transcription of adrenergic-induced genes in rat pinealocytes. We found that treatment of pinealocytes with trichostatin A (TSA), a histone deacetylase inhibitor, caused hyperacetylation of histone H3 (H3) Lys14 at nanomolar concentrations. Hyperacetylation of H3 was also observed after treatment with scriptaid, a structurally unrelated histone deacetylase inhibitor. The effects of TSA and scriptaid were inhibitory on the adrenergic induction of arylalkylamine-n-acetyltransferase (aa-nat) mRNA, protein, and enzyme activity, and on melatonin production. TSA at higher concentrations also inhibited the adrenergic induction of mapk phosphatase-1 (mkp-1) and inducible cAMP early repressor mRNAs. In contrast, the effect of TSA on the norepinephrine induction of the c-fos mRNA was stimulatory. Moreover, the effect of TSA on adrenergic-induced gene transcription was dependent on the time of its addition; its effect was only observed during the active phase of transcription. Chromatin immunoprecipitation with antibodies against acetylated Lys14 of H3 showed an increase in DNA recovery of the promoter regions of aa-nat, mkp-1, and c-fos after treatment with TSA. Together, our results demonstrate that histone acetylation differentially influences the transcription of adrenergic-induced genes, an enhancing effect for c-fos but inhibitory for aa-nat, mkp-1, and inducible cAMP early repressor. Moreover, both inhibitory and enhancing effects appear to be mediated through specific modification of promoter-bound histones during gene transcription.
在本研究中，我们调查了组蛋白乙酰化对大鼠松果体细胞中肾上腺素能诱导基因转录的影响。我们发现，用组蛋白去乙酰化酶抑制剂曲古抑菌素A（TSA）处理松果体细胞，在纳摩尔浓度下会导致组蛋白H3（H3）赖氨酸14的高度乙酰化。在用结构不相关的组蛋白去乙酰化酶抑制剂司立他汀处理后，也观察到了H3的高度乙酰化。TSA和司立他汀的作用对芳基烷基胺 - N - 乙酰基转移酶（aa - nat）mRNA、蛋白质和酶活性的肾上腺素能诱导以及褪黑素的产生具有抑制作用。更高浓度的TSA还抑制丝裂原活化蛋白激酶磷酸酶 - 1（mkp - 1）和诱导型环磷酸腺苷早期阻遏物mRNA的肾上腺素能诱导。相比之下，TSA对去甲肾上腺素诱导c - fos mRNA的作用具有刺激作用。此外，TSA对肾上腺素能诱导基因转录的作用取决于其添加时间；其作用仅在转录的活跃期观察到。用抗H3乙酰化赖氨酸14的抗体进行染色质免疫沉淀显示，TSA处理后aa - nat、mkp - 1和c - fos启动子区域的DNA回收率增加。总之，我们的结果表明，组蛋白乙酰化对肾上腺素能诱导基因的转录有不同影响，对c - fos有增强作用，但对aa - nat、mkp - 1和诱导型环磷酸腺苷早期阻遏物有抑制作用。此外，抑制和增强作用似乎都是通过基因转录过程中启动子结合组蛋白的特异性修饰介导的。
