Transient activation of transgene expression by hydrodynamics-based injection may cause rapid decrease in plasmid DNA expression

被引：40

作者：

Ochiai, H. ^{[1
]}

Fujimuro, M. ^{[1
]}

Yokosawa, H. ^{[1
]}

Harashima, H. ^{[1
]}

Kamiya, H. ^{[1
]}

机构：

[1] Hokkaido Univ, Fac Pharmaceut Sci, Kita Ku, Sapporo, Hokkaido, Japan

来源：

GENE THERAPY | 2007年 / 14卷 / 15期

基金：

日本学术振兴会;

关键词：

exogenous DNA; histones; intranuclear disposition; silencing; hydrodynamics-based injection;

D O I：

10.1038/sj.gt.3302970

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

The intranuclear disposition of exogenous DNA is quite important for the therapeutic effects of the administered DNA. The expression efficiency from one copy of exogenous DNA delivered by hydrodynamics-based injection dramatically decreases over time, and this 'silencing' occurs without CpG methylation. In this study, naked luciferase-plasmid DNA was delivered into mouse liver by hydrodynamics-based injection, and modifications of the histones bound to the plasmid DNA were analyzed by a chromatin immunoprecipitation (ChIP) analysis. In addition, the effects of a second hydrodynamics-based injection on the expression from the plasmid DNA were examined. The ChIP analysis revealed that the modification status of histone H3 remained constant from 4 h to 4 weeks. Surprisingly, the injection of saline without DNA enhanced the luciferase expression from the preexisting DNA administered 4 and 14 days previously. Our results suggest that histone modification plays no role in the silencing. Instead, our data suggest that the transgene expression is activated by the hydrodynamics-based injection manipulation, and that the return from the activated status causes the silencing.

引用

页码：1152 / 1159

页数：8

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