Novel strategy for activating gene expression through triplex DNA formation targeting epigenetically suppressed genes†

IF 4.2 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
Ryotaro Notomi, Shigeki Sasaki and Yosuke Taniguchi
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Abstract

Triplex DNA formation is a useful genomic targeting tool that is expected to have a wide range of applications, including the antigene method; however, there are fundamental limitations in its forming sequence. We recently extended the triplex DNA-forming sequence to methylated DNA sequences containing 5mCG base pairs by developing guanidino-dN, which is capable of recognizing a 5mCG base pair with high affinity. We herein investigated the effect of triplex DNA formation using TFOs with guanidino-dN on methylated DNA sequences at the promoter of the RASSF1A gene, whose expression is epigenetically suppressed by DNA methylation in MCF-7 cells, on gene expression. Interestingly, triplex DNA formation increased the expression of the RASSF1A gene at the transcript and protein levels. Furthermore, RASSF1A-activated MCF-7 cells exhibited cell growth suppressing activity. Changes in the expression of various genes associated with the promotion of apoptosis and breast cancer survival accompanied the activation of RASSF1A in cells exhibited antiproliferative activity. These results suggest the potential of increases in gene expression through triplex DNA formation as a new genomic targeting tool.

Abstract Image

Abstract Image

通过针对表观遗传抑制基因的三重 DNA 形成激活基因表达的新策略
三重 DNA 形成是一种有用的基因组靶向工具,预计将有广泛的应用,包括抗原法;然而,其形成序列存在根本性的限制。最近,我们通过开发能够高亲和力识别 5mCG 碱基对的鸟苷-dN,将三联体 DNA 形成序列扩展到含有 5mCG 碱基对的甲基化 DNA 序列。在 MCF-7 细胞中,RASSF1A 基因的表达受到 DNA 甲基化的表观遗传学抑制。我们在此研究了使用带有胍基-dN 的 TFO 在 RASSF1A 基因启动子的甲基化 DNA 序列上形成三重 DNA 对基因表达的影响。有趣的是,三重 DNA 的形成增加了 RASSF1A 基因在转录本和蛋白质水平上的表达。此外,RASSF1A 激活的 MCF-7 细胞具有抑制细胞生长的活性。细胞中与促进细胞凋亡和乳腺癌存活有关的各种基因的表达变化伴随着 RASSF1A 的激活而表现出抗增殖活性。这些结果表明,通过形成三重 DNA 增加基因表达有可能成为一种新的基因组靶向工具。
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来源期刊
CiteScore
6.10
自引率
0.00%
发文量
128
审稿时长
10 weeks
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