组蛋白乙酰化与癌症

由于组蛋白被修饰所引起的染色质结构的改变,在真核生物基因表达调控中发挥着重要的作用,这些修饰主要包括甲基化、乙酰化、磷酸化和泛素化等,其中组蛋白乙酰化尤为重要.组蛋白乙酰转移酶（HAT）和组蛋白去乙酰化酶（HDAC）参与决定组蛋白乙酰化状态.HAT通常作为多亚基辅激活物复合体的一部分,催化组蛋白乙酰化,导致染色质结构的松散、激活转录;而HDAC是多亚基辅抑制物复合体的一部分,使组蛋白去乙酰化,导致染色质集缩,并抑制基因的转录. 编码这些酶的基因染色体易位易于导致急性白血病的发生.另一方面,已经确定了一些乙酰化修饰酶的基因在染色体上的位置,它们尤其倾向定位于染色体的断裂处.综述了HAT和HDAC参与的组蛋白乙酰化与癌症发生之间关系的最新进展,以期进一步阐明组蛋白乙酰化修饰酶的生物学功能以及它们在癌症发生过程中的作用.     

Effect of 27nt small RNA on endothelial nitric-oxide synthase expression

We have reported previously that the 27nt repeat polymorphism in endothelial nitric-oxide synthase (eNOS) intron 4-a source of 27nt small RNA-inhibits eNOS expression. In the current study, we have investigated how 27nt small RNA suppresses eNOS expression. Using a chromatin immunoprecipitation assay, we examined histone acetylation in the 27nt repeat element of eNOS intron 4, the promoter region up to -1486 bp, and the 5' enhancer region (-4583/-4223bp) in human aortic endothelial cells (HAECs) treated with 27nt RNA duplex. 27nt RNA duplex induced hyperacetylation in H3 (lysine8, 12, and 23) and H4 (lysine 9 and 12) at the 27nt repeat element, which then interacted with nuclear actin, histone deacetylase 3 (HDAC3), and NonO proteins. In contrast, the histone H3 and H4 became hypoacetylated at the eNOS core promoter. HAECs treated with 27nt RNA duplex had reduced eNOS expression, but treatment with either HDAC3 small interfering RNA or NonO siRNA significantly attenuated the 27nt small RNA-induced suppression. We further found that 27nt small RNA induced DNA methylation in a region approximately 750nt upstream of the intron 4 repeats, and a methyltransferase inhibitor reversed the effect on methylation and eNOS expression. Our study demonstrates that 27nt small RNA may suppress eNOS expression by altering histone acetylation and DNA methylation in regions adjacent to the 27nt repeat element and core promoter.