Chittur Sridar V, Sangster-Guity Niquiche, McCormick Paulette J
Center for Functional Genomics, University at Albany, State University of New York, Cancer Research Center, One Discovery Drive, Rm 310, Rensselaer, NY 12144, USA.
BMC Genomics. 2008 Oct 29;9:507. doi: 10.1186/1471-2164-9-507.
Eukaryotic gene expression is a complex process involving multiple cis and trans activating molecules to either facilitate or inhibit transcription. In recent years, many studies have focused on the role of acetylation of histone proteins in modulating transcription, whereas deacetylation of these same proteins is associated with inactivation or repression of gene expression. This study explores gene expression in HepG2 and F9 cell lines treated with Trichostatin A (TSA), a potent histone deacetylase inhibitor.
These experiments show that TSA treatment results in clear repression of genes involved in the cholesterol biosynthetic pathway as well as other associated pathways including fatty acid biosynthesis and glycolysis. TSA down regulates 9 of 15 genes in this pathway in the F9 embryonal carcinoma model and 11 of 15 pathway genes in the HepG2 cell line. A time course study on the effect of TSA on gene expression of various enzymes and transcription factors involved in these pathways suggests that down regulation of Srebf2 may be the triggering factor for down regulation of the cholesterol biosynthesis pathway.
Our results provide new insights in the effects of histone deacetylases on genes involved in primary metabolism. This observation suggests that TSA, and other related histone deacetylase inhibitors, may be useful as potential therapeutic entities for the control of cholesterol levels in humans.
真核基因表达是一个复杂的过程，涉及多个顺式和反式激活分子来促进或抑制转录。近年来，许多研究集中在组蛋白乙酰化在调节转录中的作用，而这些相同蛋白质的去乙酰化与基因表达的失活或抑制有关。本研究探讨了用曲古抑菌素A（TSA）处理的HepG2和F9细胞系中的基因表达，TSA是一种有效的组蛋白脱乙酰酶抑制剂。
这些实验表明，TSA处理导致胆固醇生物合成途径以及包括脂肪酸生物合成和糖酵解在内的其他相关途径中涉及的基因明显受到抑制。在F9胚胎癌模型中，TSA下调了该途径中15个基因中的9个，在HepG2细胞系中下调了15个途径基因中的11个。对TSA对这些途径中各种酶和转录因子基因表达影响的时间进程研究表明，Srebf2的下调可能是胆固醇生物合成途径下调的触发因素。
我们的结果为组蛋白脱乙酰酶对参与初级代谢的基因的影响提供了新的见解。这一观察结果表明，TSA和其他相关的组蛋白脱乙酰酶抑制剂可能作为控制人类胆固醇水平的潜在治疗实体。
