Institute of Parasitology, University of Zürich, Zürich, Switzerland.
Mol Microbiol. 2010 Apr;76(1):48-67. doi: 10.1111/j.1365-2958.2010.07062.x. Epub 2010 Feb 1.
Histone modification is an important mechanism regulating both gene expression and the establishment and maintenance of cellular phenotypes during development. Regulation of histone acetylation via histone acetylases and deacetylases (HDACs) appears to be particularly crucial in determining gene expression patterns. In this study we explored the effect of HDAC inhibition on the life cycle of the human pathogen Giardia lamblia, a highly reduced parasitic protozoan characterized by minimized cellular processes. We found that the HDAC inhibitor FR235222 increased the level of histone acetylation and induced transcriptional regulation of approximately 2% of genes in proliferating and encysting parasites. In addition, our analyses showed that the levels of histone acetylation decreased during differentiation into cysts, the infective stage of the parasite. Importantly, FR235222 treatment during encystation reversed this histone hypo-acetylation and potently blocked the formation of cysts. These results provide the first direct evidence for epigenetic regulation of gene expression in this simple eukaryote. This suggests that regulation of histone acetylation is involved in the control of Giardia stage differentiation, and identifies epigenetic mechanisms as a promising target to prevent Giardia transmission.
组蛋白修饰是一种重要的调控机制，可调节基因表达以及胚胎发育过程中细胞表型的建立和维持。组蛋白乙酰化通过组蛋白乙酰转移酶和去乙酰化酶（HDACs）的调节，似乎在决定基因表达模式方面尤为重要。在这项研究中，我们探讨了 HDAC 抑制对人类病原体蓝氏贾第鞭毛虫生命周期的影响，蓝氏贾第鞭毛虫是一种高度简化的寄生原生动物，其细胞过程最小化。我们发现，HDAC 抑制剂 FR235222 增加了组蛋白乙酰化水平，并诱导增殖和囊形成寄生虫中约 2%的基因的转录调控。此外，我们的分析表明，在分化为囊（寄生虫的感染阶段）的过程中，组蛋白乙酰化水平降低。重要的是，囊形成期间的 FR235222 处理逆转了这种组蛋白低乙酰化，并有力地阻止了囊的形成。这些结果为该简单真核生物中基因表达的表观遗传调控提供了首个直接证据。这表明组蛋白乙酰化的调节参与了贾第鞭毛虫阶段分化的控制，并确定了表观遗传机制作为预防贾第鞭毛虫传播的有希望的靶点。
